Origin

To save time
All the SEQ questions here are past papers starting from a long time back (Proper + Repeat)
If questions repeated > Combined all the point in both answers into one question
No questions are duplicated
Made an answer plan for most questions to help save time

● Red Topics = Most important. Repeated more than 3 times / Highlighted as important
● Purple Topics - Moderate importance. Repeated once to thrice
● Blue topics - Seen only once

● Red Points - Keywords

● Blue Points - Also Keywords
● Green Text - Answer Plan

Infectious Module

Beta Lactams
Action of Benzylpenicillin
Precautions in Benzylpenicillin administration
Prescribing Benzylpenicillin in AKI
Amoxicillin given with Clavulanic acid
Imipenem and cilastatin in severe sepsis
Benzylpenicillin + Gentamicin Drug Interactions
Co-amoxiclav with Clarithromycin

Aminoglycosides and Quinolones

Drug monitoring in gentamicin therapy
Once daily dosing vs multiple daily dosing of gentamicin
Gentamicin action
Gentamicin precautions
Blood samples in gentamicin therapy
 Loading dose of gentamicin unchanged but maintenance dose changed in renal failure
Ciprofloxacin not used in acute cystitis

Tetracyclines, Macrolides and Sulfonamides

Azithromycin over Erythromycin
Clarithromycin
Sulfonamide - Trimethoprim interaction

Tuberculosis
Anti TB drug regimen
Anti TB drug S/E

Concentration dependant killing

Time dependant killing

Antimalarials
Uncomplicated vivax treatment
Malaria chemoprophylaxis
Malaria precautions
Antimalarial drugs compared in a table
Management of Malaria

Introductory Module

Pharmacokinetics and Pharmacodynamics

Therapeutic Index
First Pass Metabolism
Dose Response curve
Partial Agonist
Competitive Antagonism
 Antagonist
Zero Order Kinetics
First Order Kinetics
Agonist
Volume of distribution of a drug
Drug Tolerance
Half life and Renal clearance
Short note on drugs acting on receptors

Drug Interactions
Inducers and Inhibitors of Hepatic Enzymes
Drug interactions common in low therapeutic index drugs
(Bunch of interactions with examples)
Digoxin - Rifampicin
OCP - Rifampicin
Theophylline - Erythromycin
Type A vs Type B adverse reactions
Why zero order kinetic drugs are more likely to develop drug interactions
Short note on drug interactions
Phenytoin toxicity in liver disease

Others
Drug administration in neonates
IV NaHCO3 in Aspirin poisoning
Role of Pyridostigmine in Myasthenia Gravis
Salbutamol is used to treat hyperkalemia

CVS Module

ACEI in HTN and HF

Role of ACEI in hypertension
 Role of ACEI in heart failure
Dry cough with enalapril but not losartan
Drugs used in HTN
Drugs used in HF
Table comparing antihypertensive drugs

Anti-Anginal Drugs
Role of GTN in angina
Advice on usage and storage of GTN
Anti anginal drugs in general (Calcium CB)
Role of B-Blockers in the relief of angina
Comparing Beta Blockers

Acute Coronary Syndromes

Management of STEMI
- Immediate management
- 24 - 48 hour management
- Long term management
Management of a NSTEMI or Unstable Angina
Long term management of a STEMI (detailed)
Advising a patient after discharge

Antiplatelets, Anticoagulants and Antifibrinolytics

Antifibrinolytics and Fibrinolytics
- Tenecteplase is preferred over streptokinase
- Contraindications in thrombolytic therapy
- EXTRA - Indications for Thrombolytic Therapy

Anticoagulants
- UFH vs LMWH Credits to Praveen
- Role of enoxaparin in thrombolysis
 - Role of Warfarin as a long term anticoagulant

Antiplatelets
- Aspirin and clopidogrel in MI

Diuretics
Table Comparing Diuretics
Furosemide in CCF

Lipid Lowering Drugs

Mechanism of Atorvastatin
Precautions before starting statins

Writing Discharge Prescriptions

- STEMI
- CAP
- CAP
- STEMI
- ASA
- BA

RS Module
Immediate Management of Acute Severe Asthma
Role of Salbutamol in the management of Acute Severe Asthma
Role of Steroids in treatment of Asthma
Role of Ipratropium in the management of Acute Severe Asthma
Magnesium Sulfate in Acute Severe Asthma
Compare Salbutamol v Salmeterol v Formoterol
Advice a patient using an MDI
Preventer, Reliever and Add on therapy (Anil Sir’s Flowchart)
Essay on a patient who had failed to control her symptoms
Rx of mild persistent asthma

Question on drug interactions in an asthma prescription

Repeat - Asthma Management
Repeat - Why Formoterol is better than Salmeterol
Differences in management of Asthma vs COPD

Medicolegal and Mental Health

Classification of antidepressants
Side effects of antidepressants
Serotonin Syndrome after antidepressants

Mechanism of action of Benzodiazepines

How to advice a patient prescribed on Benzodiazepines
Why Diazepam is prescribed in insomnia

Side effects of typical vs atypical Antipsychotics

Basis of Neuroleptic Malignant Syndrome following Antipsychotic use

Role of Atropine in treating Bradycardia in Yellow Oleander poisoning

Role of Atropine in the management of Organophosphate poisoning

Mechanism of acute PCM poisoning

Management of Acute PCM Poisoning
NAC in PCM poisoning
Methanol and Iron Poisoning

<<28TH Batch Paper>>

Notes
Histamine receptors
Effects of Ach
Adrenergic receptors
Drug development
Prescribing in Children and Elderly
Antiviral Drugs
Antifungal Drugs
Immunomodulators and Immunosuppressants

Tute Questions Note Done Above

Volume of distribution (done again)
Upregulation and downregulation
Dobutamine in cardiogenic shock
Indications of anticholinergics
Antihistamines
Antifungals
HIV drugs therapy
Antivirals
IV Penicillin precautions
Renal Clearance of Benzylpenicillin exceeds GFR
Doxycycline should not be administered with calcium tablets
Nitrofurantoin is not prescribed for upper UTIS
Choosing an anticoagulant
Management of Atrial fibrillation
HTN in the healthy
HTN with B/L Renal Artery Stenosis
HTN in pregnancy
HTN with DM and CCF
HTN with NSTEMI
Heart Failure

INFECTIOUS
Beta Lactams

A 10-year-old child presented with migratory polyarthritis and a high ASOT (AntiStreptolysin O titer)
was diagnosed with rheumatic fever. On discharge he was started on intramuscular benzathine
penicillin every 3 weeks.

a) Explain the pharmacological basis of giving benzathine penicillin every 3 weeks to this patient.
(30 marks)

PLAN
● What is Rheumatic Fever?
● Introduce Benzylpenicillin
● Why is it special (2-4 weekly dosage)
● Action of benzylpenicillin
● Other points (Probenecid, Compliance)
Rheumatic fever is an immune mediated multisystem inflammatory disease that classically occurs
following pharyngeal infection by Group A Streptococci (GAS).

Having had an episode of rheumatic fever, this child is now at a higher risk of developing recurrent
episodes.

Ongoing and repeated episodes of acute rheumatic fever causes inflammatory changes involving heart
valves, eventually progressing to rheumatic heart disease.

Therefore, he should receive antibiotics sensitive to Group A Streptococci as secondary long-term

prophylaxis for rheumatic fever.

Benzathine penicillin is a natural penicillin and the IM form of benzyl penicillin (penicillin G) that allows
prolonged low concentrations of antibiotic action over 2–4 weeks. (administered every 2-4 weeks)

Therefore, even after three weeks of the single IM injection (of 1.2 million units), adequate drug levels
in blood and tissues will be maintained to give the antimicrobial activity.

Benzyl Penicillin is a natural narrow spectrum penicillin which is mainly effective against gram positive
bacteria such as streptococcus spp.

They act by inhibiting the enzymes involved in peptidoglycan cross linking (penicillin binding proteins) of
the bacterial cell wall. This causes weakening of the bacterial cell wall causing osmotic rupture and kills
bacteria (bactericidal).

Therefore, benzathine penicillin is an effective prophylactic treatment for GAS infection which also has
the added benefit of improved patient compliance as it can be given every three weeks compared to
giving daily oral penicillin.

Probenecid can also be used simultaneously with Penicillin G to increase levels in blood (by impairing
renal excretion)

Benzylpenicillin action is tend to get inhibited by the bacterial mechanisms such as,
 - Beta lactamase production
- Modification of Penicillin binding proteins
- Reduction of the permeability of the outer layer
- Possession of pumps in the outer layer which remove the beta lactams
They tend to cause serious adverse effects too, such as allergies.

(b) Name the life - threatening side effect caused by Benzathine penicillin (5 marks)
Anaphylaxis

(c) List the precautions to be taken regarding the side effect mentioned in (a) (10 marks)

● Before administration asking whether the patient has any allergy, especially any drug allergy.

● Avoid giving the drug if there is a history of penicillin allergy

● Performing intradermal test for penicillin allergy and if a flare and wheal response occurs
(positive response) avoid penicillin.

● Having 1:1000, 0.5 ml adrenaline ready to give immediately if anaphylaxis occurs.

● Monitoring the patient for some time after the injection for anaphylactic symptoms: urticaria,
angioedema, reduced blood pressure, breathing difficulty, persistent GI symptoms

● If the allergy history is vague/ not clear, perform a skin prick test before prescribing the drug

● Advice the patient to immediately withdraw/ stop the drug use if he experiences sudden onset
breathing difficulty, hypotension, pruritus/ itching and attend the hospital immediately.

● Keep an injectable epi pen to be used at emergencies in allergy susceptible individuals.

(these are very expensive)
(d) He was found to be allergic to benzathine penicillin during the fifth visit and it was decided to
change the prophylaxis to a macrolide.

Prescribing benzyl penicillin to a 35 year old man with leptospirosis complicated by acute kidney
injury. (25 marks)

Leptospirosis is caused by Leptospira spp (2)

Benzyl penicillin is a β- lactam (2) antibiotic that interferes with the bacterial cell wall synthesis by
inhibiting the enzymes involved in peptidoglycan cross linking. (4) leading to osmotic rupture (1) It is
bactericidal (2) and shows time-dependent killing (1) Leptospira spp are sensitive to benzyl penicillin. (2)

But benzyl penicillin is excreted solely by the kidneys, mainly by active tubular secretion. (4) Severely
impaired renal functions can result in adverse effects like GI disturbances, hypersensitivity, haemolytic
anemia, seizures etc. due to prolongation of half-life and the concentration of the drug in the body(4)

So in a case of renal impairment, the doses should be reduced or the drug should be replaced. (3) An
alternative such as a macrolide should be chosen as they are solely excreted in bile and kidneys.

Describe the pharmacological basis for the use of following antibiotic combinations in the given
conditions.

Amoxicillin and clavulanic acid in community acquired pneumonia (30 marks)

PLAN
- Definition of CAP
- Amoxicillin function
- B Lactamase enzyme
- Function of Clavulanic Acid
Community acquired pneumonia is inflammation of lungs characterized by cough, fever, SOB (2) mainly
caused by Streptococcus pneumonia, Haemophilus influenzae (1)

Amoxicillin is an extended spectrum (amino) penicillin (3) that inhibits cell wall synthesis by interfering
with the cross linking of the peptidoglycan layer (4). It shows time-dependent bactericidal action. (3)

Amoxicillin is susceptible to hydrolysis by beta lactamases, (3) so is resisted by β lactamase producing

agents. (2) Above mentioned bacteria produce beta lactamases thus giving amoxicillin alone is not
effective (2)

Clavulanic acid is a beta lactamase inhibitor (3). Binds irreversibly with β-lactamases causing suicidal
inhibition of beta lactamases (3).

Therefore, clavulanic acid can be used in combination with Amoxicillin to destroy organisms (3) like S.
pneumoniae and H. influenzae. This combination is known as Co-amoxiclav (1)

Imipenem and cilastatin in severe sepsis. (25 marks)

In severe sepsis, treatment should be initiated as soon as possible even before the specific pathogen is
identified. (2)

Here, empirical therapy should be used. Empirical therapy is the use of a combination/ broad spectrum
therapy that covers all likely pathogens, before the infecting organism has been identified. (3)

Imipenem is a carbapenem (β lactam) with bactericidal action. (4)

Shows a very broad spectrum of action - is effective against most gram +/- pathogens (3) (resist most
beta lactamases except metallo-β-lactamases, MRSA and enterococci) It also has a good tissue
distribution. (2)

But Imipenem when given alone is cleaved and inactivated by dehydropeptidase in the PCT (3) to
products that are toxic to renal tubules. (2)
Cilastatin is a dehydropeptidase inhibitor and prevents the cleavage of imipenem. (4)

Therefore, in severe sepsis, imipenem is combined with cilastatin to prevent both inactivation and
toxicity and prolong the antibiotic effect. (2)

A 24-year old woman diagnosed with uncomplicated infective endocarditis was treated with
benzylpenicillin 3 million IU IV 4 hourly and gentamicin 1 mg/kg IV 8 hourly for 2 weeks
Briefly explain two (2) drug interactions between benzylpenicillin and gentamicin (20 marks)

PLAN
- Definition of a drug interaction
- Functions of both drugs
- Synergistic effect
- In-Vitro inactivation

If the response of one drug is altered by administering a second drug, a drug - drug interaction is said to
have taken place. (2) They may be harmful, beneficial or clinically insignificant. (1) Pharmacologically
They can be pharmacodynamics, pharmacokinetic or pharmaceutical drug interactions. (1)

Benzyl penicillin is a β lactam antibiotic

Acts by weakening the bacterial cell wall
- By inhibiting peptidyl transferase
- That catalyzes cross linking of peptidoglycan layers.(2)
- Osmotic gradient between inside and outside is lost resulting in rupture of the cell.
Time dependent killing. (1)

Gentamicin is an aminoglycoside
Irreversibly inhibits bacterial protein synthesis
Binding to 30s ribosomal subunits.(2)
Concentration dependent killing (1)
Entry of gentamicin into bacterial cytoplasm is enhanced by the cell wall weakening action of benzyl
penicillin.(3) Hence these two drugs act synergistically through a pharmacodynamic drug interaction. (1)
So that the action of the gentamicin will be multiplied rather than being addictive. This is beneficial in
treatment of infective endocarditis.(1)

Benzyl penicillin will inactivate gentamicin under in- vitro conditions.(3) Hence they should never be
mixed in the same solution. (1) This is a harmful pharmaceutical drug interaction. (1)

Briefly explain why renal clearance of benzyl penicillin exceeds the glomerular filtration rate (20
marks)

Renal clearance of a drug is the volume of blood completely cleared of that drug per unit time (5) by the
kidney. (2) {for specifically defining renal clearance}

If a drug is only excreted by filtration from the kidneys, clearance is equal to the Glomerular Filtration
Rate (GFR). (5)

Benzylpenicillin is a beta lactam antibiotic (3), which is mainly cleared by the kidney through secretion
into renal tubular fluids. (5) So secretion will lead to excretion of a higher amount of drug exceeding the
GFR.

Aminoglycosides and Quinolones

Explain why plasma concentration monitoring is important with gentamicin therapy (40 marks)

PLAN
- General use of monitoring - Avoid subtherapeutic, toxic, efficacy
- Toxicity is time and conc dependent
 - MIC in concentration dependant antibiotics
- Recalculation of gentamicin conc in impaired renal function
- Describe the S/E profile

Plasma concentration monitoring of a drug is needed to avoid sub therapeutic levels (1) and toxicity (1)
thereby ensuring therapeutic efficacy. (1)

Gentamicin is a bactericidal aminoglycoside, showing concentration dependent killing (2). Therefore the
rate and extent of killing will increase with increasing drug concentrations (1). Since gentamicin has a
narrow therapeutic index (3), plasma drug concentrations should be maintained at a narrow range to
prevent toxicity (2).Toxicity is both time and concentration dependent.(2) Toxicity is unlikely to occur
until a certain threshold concentration is reached (2)and the time period above this concentration
should be longer enough to cause toxicity (2).The toxic levels increase the adverse effects of gentamicin
nephrotoxicity and irreversible ototoxicity (1). Therefore plasma concentration monitoring is important
in all who receive gentamicin therapy to ensure its bactericidal action(1) and to prevent toxicity
especially at high doses, in those with renal impairment, elderly and when used for more than 5 days (1)

Bacterial killing of gentamicin is dependent on the concentration of the antibiotic at the site of the
infection. Bacterial killing is dose dependent. The minimal inhibitory concentration is the lowest
concentration of an antimicrobial that will inhibit the visible growth of a microorganism after an
overnight incubation. In a concentration dependent killing antibiotic such as gentamicin the MIC is
determined by the area under the TIme - Concentration curve. This must be maintained at an adequate
level and hence subtherapeutic levels (where the conc of drug is not enough to elicit a response) should
be avoided.

Gentamicin is renally cleared by glomerular filtration. (1) So in those with renal impairment, the
clearance is reduced (1) thereby increasing the half-life, bioavailability and chances of toxicity.(2) Hence
the dose is determined based on the patient’s weight and renal function. (1) Peak and trough
concentration both needed to be measured when monitoring the plasma concentration (2) Hence
therapeutic drug monitoring is important with gentamicin therapy.

Gentamicin has a serious side effect profile. Ototoxicity (irreversible) and nephrotoxicity (reversible if
stopped early)
Once daily dosing of gentamicin is as effective but less toxic than multiple daily dosing (30m)

PLAN
- Intro to drug
- Why is single dose possible
- Rapid killing spike
- Post antibiotic effect
- Less likely to be toxic (Minimized time over threshold)
- SSD - Less labor intensive + Outpatient
Gentamicin is an Aminoglycoside drug (1) which acts against gram positive and negative organisms. Act
by inhibiting protein synthesis. (1) They are water soluble drugs that do not cross cell membranes.
Therefore administered IV/IM.

Gentamicin is given as both a single daily dose regime and as multiple daily doses. Single daily dosing of
Gentamicin is possible due to,
1. Concentration dependent kinetics (2)
2. Post antibiotic effect (2)

In concentration dependent kinetics, increasing concentrations of the drug kills an increasing proportion
of bacteria at a more rapid rate. (2). In single large daily dosing immediate high plasma concentrations of
the drug is achieved.(1) This result in more rapid killing of bacteria compared to multiple small doses.(1)

Effectiveness
● Post antibiotic effect, means that the antibacterial activity persists beyond the time which
measurable drug concentration is present (2)
● This lasts for several hours in aminoglycosides which renders once daily dosing (1)

Gentamicin toxicity is a serious complication of the drug. It can lead to mainly ototoxicity and
nephrotoxicity (1) Less toxicity in single daily dosing is because (1)
● Toxicity of aminoglycosides is both time and concentration dependent.(2)
● Toxicity is unlikely to occur until a certain threshold concentration is reached.
● But once the concentration is achieved the time beyond this threshold becomes critical (2).
(A trough concentration of 2mcg/ml is predictive of toxicity.)
 ● This time beyond the toxic threshold can be minimized in once daily dosing regimens. (1)

When SSD is given concentration rapidly goes up and rapidly comes down, But as there’s PAE
antibacterial effect persists without the toxicity (1)
The main aim is to give more time at lower trough concentrations with less toxicity.(2)

In Multiple daily dosing,

● The total time above the toxic threshold is greater than a single large dose therefore more risk of
toxicity.(2)
● In addition, the amount of reabsorption of the drug at PCT is less in single daily dosing as
reabsorbing transports reach a saturation limit (1). This reduces the risk of toxicity.
● SDD is less labor intensive (1.5)
● SDD is more feasible for outpatient therapy (1.5)

Describe the mechanism of action of gentamicin

PLAN = Intro - Entry - Killing action - Resistance - PAE/CDK

Aminoglycoside
Bactericidal
Concentration dependent killing

Gentamicin enters the cell via the outer and inner membranes of the bacterial cell wall
● Goes across the outer layer through porin channels
By passive diffusion.

● Needs ATP to pass through the inner layer to get into the cell
Oxygen dependent manner.
Once inside the cell, it binds to 30s subunits of the ribosomal proteins and inhibits the protein synthesis
irreversibly.
1) Initiation of the protein synthesis interfered
2) Misreading of the mRNA
3) Breakup of polysomes in to non-functional monosomes
Due to the above activities, the bacterial cell dies.

The bactericidal activity is potentiated due to 2 reasons

1. Concentration dependent killing
2. Post-antibiotic effect

But some bacteria show resistance to its action via a few mechanisms.
● Aminoglycosides are inactivated by several enzymes
● Entry of the aminoglycoside is impaired
● Receptor for gentamicin in 30s subunits is deleted or altered.

Describe the precautions you would take when administering IV gentamicin.

1) Whether the patient is indicated for gentamicin to prevent unnecessary administration.

- (gram negative aerobic infections)
2) C/I excluded - Myasthenia gravis
3) Check for pre existing renal disease
4) Dosing according to the body weight and the renal functions.
5) Dehydration corrected prior
6) Administration is done on a daily basis to reduce the SE and given over 60 min
7) Auditory and vestibular function assessed
8) Potentially ototoxic drugs should be avoided – Cilastatin, furosemide
9) Side effects are common in elderly
10) Continuous blood level monitoring of the serum drug level
11) Don’t exceed 7 days IV infusion
 12) Never mixed with penicillin in-vitro
13) Avoid pregnancy due to fetal ototoxicity.
14) Interferes with neuromuscular transmission
15) Avoid Single Doses - IE
16) Burns>20%
17) Creatinine Clearance Less Than 40 Ml/min

Gentamicin is an aminoglycoside which is known to have a serious adverse effect profile.Causes

reversible nephrotoxicity, irreversible ototoxicity and impaired neuromuscular transmission.Therefore
renal functions should be assessed before starting an aminoglycoside.

State at what times the blood samples should be obtained measure to Gentamicin levels In a patient
who's on multiple dose regimen (10 marks)

Times at which blood sample should be obtained measure gentamicin levels in a patient who is on
multiple dose regimen

1) If the renal function of the patient is normal

● After 3-4 doses of regime
● Following a dose change
2) In impaired renal function it is earlier and more frequent
3) Done when used for more than 2 days.
4) Trough Concentrations-30 minutes prior to the next dose.

In a patient with creatinine clearance <30 ml/min the loading dose of gentamicin remains unchanged
while the maintenance doses are reduced.Explain.

Gentamicin Is An Aminoglycoside.
Exhibit Concentration Dependent Killing.
Gentamicin Is Eliminated By Glomerular Filtration.
In Renally impaired patients they accumulate In Renal Cortex.
Gentamicin toxicity is both concentration and time dependent.
When Giving The Same Loading Dose Toxicity Could Be Reduced (concentrations are longer)
Because if the loading dose is reduced then the next dose should be administered quickly and this will
increase the toxicity.(time with lower trough concentration is reduced).
Maintenance doses are reduced as elimination from kidneys are impaired increasing the T1/2 of
the drug.

List 2 adverse effects on gentamicin and describe how these can be minimized.

Ototoxicity
- Vestibular and auditory assessment should be done before, during and after the treatment.
- Those patients who are having pre existing disease should have altered doses.
- Potentially ototoxic drugs should be avoided – cilastatin
Nephrotoxicity
- Renal assessment should be done before the administration of the drug.
- Drugs should be administered cautiously in patients with pre-existing renal diseases, co-current
nephrotoxic drugs, conditions in which urine volume is reduced.

Explain giving reasons, whether prescribing in the following patients is rational.

Prescribing ciprofloxacin as empirical therapy to a 24 year old pregnant woman with a POA of 20
weeks who is diagnosed with cystitis (lower urinary tract infection). (20 marks)

PLAN
- Introduction to CIprofloxacin
- What is empirical therapy and indication
- Damage to growing cartilage
- Not indicated in uncomplicated cystitis
- Resistance
This is not rational (1)
Ciprofloxacin is a fluoroquinolone (3) that inhibits bacterial DNA synthesis by inhibiting bacterial DNA
gyrase activity. Shows concentration dependent bactericidal action. (4) It is a broad spectrum antibiotic
(2). Therefore, it is used for empirical therapy (1) Cystitis is mainly caused by E.coli bacteria which is a
gram negative type and therefore ciprofloxacin is given as it has an excellent gram negative coverage.

Empiric therapy is where combination/ broad spectrum antibiotics are used to cover all likely pathogens
when the infecting organism(s) have not been identified.(2) and when the initiation of treatment cannot
be prolonged any further.

Ciprofloxacin can cause damage to the growing cartilage in a fetus that results in arthropathies. (5)
Therefore, the use of ciprofloxacin should be avoided in pregnancy. (2) (as well as in infants)

(Vomiting which is a SE of ciprofloxacin could also worsen vomiting due to pregnancy)

Lecture note - Ciprofloxacin and levofloxacin should NOT be prescribed for uncomplicated cystitis.
Fluoroquinolones should also only be used if first line treatments are effective and not available.
(Increasing resistance to ciprofloxacin by E.coli strains is noted nowadays)

Tetracyclines, Macrolides and Sulfonamides

Explain why azithromycin is preferred over erythromycin considering their pharmacological properties
(15 marks)

Azithromycin and erythromycin are macrolides that inhibit bacterial protein synthesis by reversibly
binding to the 50s ribosomal subunit. They’re bacteriostatic with time dependent killing.

Azithromycin is a semi-synthetic derivative of erythromycin which has replaced it in clinical use due to
numerous reasons.

● High volume of distribution

Therefore, it will remain at the site of infection for a prolonged period compared to erythromycin as an
antimicrobial agent.

● Longer half life

The elimination of azithromycin is also prolonged resulting in a longer half-life compared to

erythromycin. Therefore, frequency of administration of azithromycin is less compared to erythromycin,
which is preferred because it improves the compliance.

● Less side effects

Compared to azithromycin, erythromycin acts on motilin receptors in the gut and stimulates gut motility
causing adverse effects like nausea, vomiting, diarrhea. These effects are less with azithromycin.

This will improve the compliance and since it’s a child, loss of appetite and frequent gastrointestinal
effects should be minimized as much as possible
.
● Less drug interactions

Erythromycin causes drug interactions by strongly inhibiting hepatic cytochrome enzymes while
azithromycin is much less likely to be involved. Therefore, azithromycin would be preferred over
erythromycin for long-term prophylaxis.

A 22 year old female patient is diagnosed with moderate community acquired pneumonia. She is
prescribed amoxicillin 500mg orally 8 hourly, and clarithromycin 500 mg orally 12 hourly for 7 days.

Describe the mechanism of action of clarithromycin.

Clarithromycin is a macrolide type antibiotic.

It act by binding to the 50 sub-unit of the bacterial ribosomes and arrest bacterial multiplication,
therefore called “bacteriostatic”
It shows a time dependent bacterial killing and has a similar antibiotic spectrum of penicillin, therefore
used as an alternative for penicillin.

Clarithromycin is mostly effective against Gram positive organisms – Haemophilus influenzae

It is metabolized mostly in the liver and rest is excreted in urine.

Explain the rationale for the prescribed antibiotic combinations.

Community acquired pneumonia is caused by inflammation in the lung parenchyma.

In young patients it is caused mainly by gram positive infections like Streptococcus pneumoniae,
Haemophilus influenzae.

Therefore when the empirical antibiotic treatments are given, both gram negative and gram positive
coverage has to be ensured.

Amoxicillin has both gram negative and positive action whereas clarithromycin has action against
Haemophilus influenzae.

Apart from that amoxicillin is a type of penicillin which acts by disrupting the bacterial cell wall.

Therefore once the cell wall is destroyed, it would be easier for clarithromycin to get into the cell to act
on the 50s subunit of the bacterial ribosomes.

List two (2) indications for clinical use of clarithromycin. (10 marks)
I Respiratory tract infections – Atypical pneumonia (Haemophilus influenzae)
II. Mild to moderate skin and soft tissue infections – Lyme disease
III. Otitis media
IV. H.pylori infections

Describe two (2) advantages of preferring clarithromycin to erythromycin in clinical use. (20 marks)
- Long Half life. Clarithromycin has a long half life which allows it to be used less frequently.
 - Low side effect profile. Vomiting, diarrhea and nausea like side effects are very common with
erythromycin rather than with clarithromycin.
- More gram negative cover

List 2 Indications For Clinical Use Of Clarithromycin

Community acquired upper and lower respiratory tract infections.
Skin and soft tissue infection erysipelas cellulitis(who's allergic to penicillin)
Chlamydial Infection
Helicobacter Pylori Infection
Pertussis
Diphtheria
Mycobacterial Infection

A 30-year-old previously healthy man is admitted to the hospital with community acquired
pneumonia. Co- amoxiclav and clarithromycin have been started as empirical therapy.

Define the term “Empirical Antibiotic Therapy” (10 marks)

Antibiotic therapy to cover all the likely pathogens (4) in a condition where the infecting organisms have
not yet been defined (2), by the use of a single broad spectrum agent (2) or combination therapy (2).

Explain the pharmacological basis for prescribing Co- amoxiclav and clarithromycin to this patient. (40
marks)

Community acquired pneumonia in adults is mainly caused by gram positive bacteria like S. pneumoniae,
G. negatives eg: H.Influenzae and atypical organisms like Mycoplasma sp.
(correct type of bacteria ie any correct example- 2x3=6 marks)

Hence antibiotics should be chosen to cover all the spectrums mentioned above.

Co- amoxiclav is a combination of Amoxicillin and clavulanic acid. (2)

Amoxicillin is an aminopenicillin which is a broad spectrum beta lactam antibiotic. (2) It acts by binding
to the Penicillin binding proteins and inhibition of cross link formation between peptidoglycan layers of
the cell wall (2) which results in inhibition of cell wall synthesis. (3) This causes osmotic lysis of the
bacteria, thereby it is bactericidal. (1)

When administered orally, it acts mainly against G.positives and G.negative rods causing community
acquired pneumonia. (2) Clavulanic acid binds to beta lactamase enzymes which are produced by
G.positives such as S.aureus and irreversibly inhibits it. (4) This protects the inactivation of amoxicillin by
beta lactamases. (2)

Can be given orally (1) with amoxicillin as Co- amoxiclav. However co-amoxiclav cannot be used against
atypical organisms such as Mycoplasma sp. As they don’t have a cell wall.(1)

Clarithromycin is a macrolide. (2) It acts on the 30S subunits of the ribosomes (2) and inhibits bacterial
protein synthesis. (3) So it acts as a bacteriostatic drug. Can be given orally. (2) It’s spectrum is mainly
similar to penicillins, so it acts against G. Positives and G. negatives as well.(1)

However most importantly it is effective against atypical organisms, which co-amoxiclav cannot be used
effectively (Such as mycoplasma as they lack a cell wall) (4) Thereby co-amoxicillin and clarithromycin
can be used as a combination to treat a patient with the community acquired pneumonia.

List three (3) adverse effects of co-amoxiclav (15 marks)

Hypersensitivity/ anaphylaxis
Thrush
Hepatic toxicity
Diarrhea
(5 marks x3 any correct adverse effects)
“Combination of sulfonamide and trimethoprim is more effective than using either agent alone” Using
your knowledge on Mechanism of action of given drugs, explain the above statement (20 marks)

Sulfonamides are competitive inhibitors (1) of dihydropteroate synthase enzyme (2) Trimethoprim is a
competitive inhibitor(1) of dihydrofolate reductase (2)

Both (1) the above enzymes are involved in the bacterial folic acid synthesis pathway (1) which is
essential for bacterial survival. Both (1) sulphonamides and trimethoprim are bacteriostatic (1) when
administered individually. (1)

Co- administration of sulphonamides and trimethoprim as in co-trimoxazole (1) has a synergistic effect
(2) The combination of the two drugs has a bactericidal action. (2) Hence the combination is much
more effective than using either drug alone. (1)

A 30 year old woman who is 6 weeks pregnant has developed acute cystitis. Name 2 oral antibiotics
which can be prescribed for these patients.
Nalidixic Acid
Methenamine
Can’t give Nitrofurantoin – contraindicated in pregnancy.
 Antimycobacterials

A 26 year old man was diagnosed with primary pulmonary tuberculosis. He was started on isoniazid
(INAH), rifampicin, pyrazinamide, and ethambutol.
Describe the pharmacological basis for prescribing the above drug combination. (30 marks)

PLAN
- What is TB
- Habitats of bacteria
- Regimes and phases
- Drugs and main uses
- Why we need to use as a combination
- DOTS

What is TB?
Tuberculosis is a disease caused by Mycobacterium tuberculosis.
Mycobacterial organisms may reside as
1) Metabolically Active bacilli inside cavities
2) Bacilli inside Cells e.g:Macrophages as Semi Dormant bacilli
3) Dormant bacilli (0.5 *4=2)

The drugs are targeted against each bacterial population.

All new patients with newly diagnosed pulmonary tuberculosis fall into category 1 of the treatment
regime (1)
Given Isoniazid, Rifampicin, Pyrazinamide and Ethambutol during the initial phase daily for two
months.(1) (Intensive Phase)
And INAH and rifampicin alone for the next four months. (1) (Continuous Phase)

Isoniazid
 ● Inhibits synthesis of mycolic acids (essential components of mycobacterial cell walls and kills the
cell) (2)
● Bactericidal drug for actively growing tubercle bacilli. (1)
● Active against both extracellular and intracellular organisms. (2)
● Isoniazid kills 90% of the total population of bacilli during the first few days of treatment (1)

Rifampicin
● Inhibits RNA synthesis (2)
● Bactericidal drug (1)
● Kills intracellular organisms and those sequestered in abscesses and lung cavities. (2)
● Active against semi dormant persisters. (1)
● Most effective sterilizing drug. (1)

Pyrazinamide
● Disrupts mycobacterial cell membrane metabolism and transport functions.(2)
● Bactericidal drug. (1)
● Acts against organisms residing in acidic environments of lysosomes (1)
● Good sterilizing drug. (1)
● Reduces duration of therapy

Ethambutol
● Interfere with mycobacterial cell wall synthesis.(2)
● Bacteriostatic drug. (1)
● Used with other agents to prevent emergence of resistance.(1)

These drugs are used in combination

To reach peak serum levels of all the drugs simultaneously to obtain the maximum bactericidal effects.
(1)
To kill actively multiplying bacilli and semi dormant persisters.(1)
To prevent emergence of drug resistant organisms.(1)
To ensure that poor compliance does not result in monotherapy with consequence to drug resistance.(1)
These drugs used in combination will rapidly kill TB bacilli and make the patient non infectious quickly
while improving the symptoms.
Mutants resistant to one drug are usually susceptible to another

If the question had

Streptomycin
● Bactericidal
● Against extracellular bacteria
● Combined with erythromycin

Directly Observed Therapy (DOT) is essential in IP for every single dose

● Ensures compliance
● Prevents development of drug resistance
Most patients - sputum smear (+) pulmonary TB become smear (-) < 2/12
Infectious patients - non-infectious <2/52

EXTRA - Continuous phase

- Fewer drugs are used compared to intensive phase
- Comparatively longer period
- Sterilizing effects of drugs ensures elimination of persistors and relapse
- At least once a week observation of drug compliance is ideal

EXTRA - Category 2
- Includes all Previously treated cases
- 3 HRZE
5 HRE

Immunocompromised - Start anti TB therapy then follow with antiretrovirals

Pregnancy any 3 drugs except streptomycin
MDR-TB resistant to Isoniazid and Rifampicin

Briefly describe what advice you would give this patient regarding side effects of anti tuberculous
drugs. (40 marks)

Patient should be advised on common side effects, when he/she should see a doctor regarding the side
effect and, what to do if side effects occurs (2)

"You may experience the following minor side effects. These Side effects cause relatively little
discomforts therefore do not stop taking the drug" (2)

Isoniazid
1. Burning sensation in feet - Take pyridoxine 100 mg daily
2. You may experience hives, itchy or flushed skin, red eyes, facial swelling (histamine reaction) -
Avoid eating red fish like Bala, kelawalla
3. CNS toxicity may respond to pyridoxine

Rifampicin
1. Anorexia, nausea, abdominal pain – Take drugs with small meals.
2. Orange/Red Urine, sputum, tears – It indicates that the drug is working therefore you need not
fear.
3. Rashes - Avoid heaty fish
4. Take drugs just before sleeping

Pyrazinamide
1. Joint pain – Take Aspirin/ NSAIDs
(3*5=15, 1.5 each for S/E and management)
(1*3 = 3, mentioning the specific drugs)
 "If you experience the following side effects stop the drugs responsible and seek medical advice as soon
as possible" (2)

In general
1. Yellowish discoloration of skin and sclera(Jaundice) – Stop anti TB drugs Most anti TB drugs
especially P, I and R)
2. Vomiting and Confusion - Stop anti TB drugs.
3. Rashes - Stop all TB drugs, reintroduce with least likely culprit

Ethambutol
1. Recent impairments of vision, red green colorblindness – Stop Ethambutol.

Rifampicin
1. Shock, Purpura, acute renal failure, hemolytic anemia – Stop Rifampicin.
(2*4=8, 1 each for S/E and management)
(1*2 =2, mentioning specific drugs)

Additionally,
● Ask for any other drugs he is on e.g.: Warfarin, Anticonvulsants, corticosteroids and do the
necessary dose adjustments.(2)
● Oral contraceptives (in a woman) should be changed to an alternative method.(2)
● Periodic liver function tests and visual acuity testing is advised during
treatment.(2)

Isoniazid Immunological reactions (Fever, rashes and SLE- Histamine effects)

Hepatitis is a serious effect
Peripheral neuropathy
- Structural analogue of pyridoxine
 - Increased pyridoxine excretion
- Relative pyridoxine deficiency
- Reversibly by administering pyridoxine
CNS Toxicity
Hematological abnormalities

Rifampicin Orange colored urine, sweat, tears (reversible and indicated drug is working)
Elevation of serum transaminases and bilirubin (common, continue treatment)
Asymptomatic jaundice

Six Toxicity Syndromes

● Influenza like syndrome
● Abdominal syndrome
● Respiratory syndrome
● Shock
● Acute Renal Failure
● Acute Hemolytic Anemia and Thrombocytotic Purpura

Potent enzyme inducer of P450

Pyrazinamide Joint pain (Managed by NSAIDS)

Hyperuricemia

Ethambutol ● Optic neuritis (Reversible if stopped early or may go blind)

● Note history of disease before starting treatment
● NOT given to patients with reduced vision
● Alternatives chosen for patients who cannot understand
● Regularly assess vision
● Stop if further deterioration
Streptomycin (Common aminoglycoside side effects)
But serious
Itch with rash
Deafness
Dizziness, Vertigo, Nystagmus
Exclude in pregnancy - CVIII damage

First line anti tuberculous drugs that are commonly hepatotoxic

● Pyrazinamide (most hepatotoxic)
● Isoniazid
● Rifampicin (least hepatotoxic)
Jaundice is a S/E of all drugs

Define the post antibiotic effect (10 marks)

Persistent suppression of bacterial growth (3)

Even after the drug concentration has fallen below the MIC
Even when there isn’t a measurable drug concentration (2) is post antibiotic effect.
This effect is concentration dependent. (3)
Aminoglycosides (1) and quinolones (1) show post antibiotic effect

Concentration dependent killing. (25 marks)

Killing of bacteria depends on the antibiotic concentration at

the site of infection. (5)
Rate of killing increases with increasing drug concentrations,
until a critical value. (2)
Once the maximum concentration is reached
 Further increment of dose will not increase the bacterial killing
Will cause more side effects. (5)
Aminoglycosides, Metronidazole (4x2=8)
(5 marks) (2 correct for MIC and Cmax)
Time dependent killing (25 marks)

In time dependent killing, bacterial killing depends on the

time duration which antibiotic levels remain elevated above
the MIC. (5)
Once the drug dose exceeds a critical value, increasing the
dose more than that will not increase the rate of bacterial
killing. (5)
For the best effect, Antibiotic levels should remain elevated
above the MIC for 40%-50% of the dosing interval. (2)
Penicillins, Cephalosporins, Monobactams etc. (4x2=8)
(5 marks)- (2 correct for MIC and Time over MIC)

Antimalarials

Describe the treatment to a patient diagnosed with uncomplicated plasmodium vivax infection.

Aim Of The Drug Therapy Is To,

Achieve CLINICAL CURE = eliminate ERYTHROCYTIC SCHIZONTS
Achieve RADICAL CURE = eliminate LIVER HYPNOZOITES
Prevent TRANSMISSION = eliminate GAMETOCYTES

Chloroquine has a clinical cure and prevents transmission.

Chloroquine inhibits the enzyme heme polymerase therefore heam produced by the parasite by
breaking down hemoglobin accumulates.

● Heme is toxic leading to the death of the parasite.

● Given for 3 days
○ 1st day-10 mg/kg
○ 2nd day-10 mg/kg
○ 3rd day-5 mg/kg

Primaquine for a radical cure of P.V

Mechanism of action is causing oxidative damage to the cells
0.25mg/kg for 14 days

C/I in pregnant and lactating women, infants, people with G6PD deficiency.

Name the drug and the dosage regimen you would prescribe for patients with uncomplicated P.F
malaria.
Treat with Artemisinin Based Combination Therapy (ACT=Artemether+Lumifantrine) for over 3 days
And a Single Dose Of Primaquine -0.75mg/kg

What's the role of primaquine in P.F Malaria?

Effective against gametocytes and preventing transmission.

Name the drug that should be given to an unconscious patient with P.F malaria and precautions you
would take when prescribing and administering this drug.

● IV Artesunate
● (IV quinine iv artesunate is not available)

Artesunate used cautiously in patients with chronic cardiac disorders as this drug will lengthen PR
interval and are not recommended in T1 pregnancy.
For Quinine monitor blood glucose,cardiac monitoring,Reduce dose in renal/hepatic impairment,

Be cautious if there is a H/O of G6PD deficiency or hypersensitivity

C/I - Myasthenia Gravis, Optic Neuritis, Tinnitus, Hemoglobinuria

Describe the management of uncomplicated P.Malaria In Pregnancy.

● Artemether is not recommended in T1 of pregnancy
● Primaquine Is Not Recommended In Pregnancy
● Therefore in T1
● Quinine Along With Clindamycin Is Given For 7 Days.
● In T2 and T3-ACT given

Describe the management of plasmodium vivax malaria and uncomplicated falciparum malaria in
pregnancy.

When managing malaria there are 4 main principles to be considered.

1. Clinical cure of the patient
2. Radical cure of the patient
3. Prevention of the transmissions
4. Chemoprophylaxis

In Plasmodium vivax malaria for the clinical cure chloroquine is given as follows.
- Day 1 – 10 mg/kg single dose
- Day 2 – 10mg/kg single dose
- Day 3 – 5 mg/kg single dose

For the radical sure and the prevention of the transmission of the disease primaquine is considered. But
as it is contraindicated in pregnancy, it is given 6 weeks following the delivery.

But till the specially during the antenatal period patients should be under close follow up to detect any
complication. Doses are as follows,
 - 0.25mg/kg for 14 days
- In G6PD deficiency – 0.75mg/kg weekly for 8 weeks under supervision

Primaquine also prevents transmission of vivax malaria.

In Plasmodium falciparum malaria for the clinical cure and radical quinine is given if the pregnancy is in
the first trimester. If the patient's pregnancy is in the 2nd or 3rd trimester coartem can be considered.

For the prevention of the transmission the same amount of primaquine dose is given as in Plasmodium
vivax malaria with the same precautions.

For either type, if a pregnant mother is going to a high risk area chemoprophylaxis should be considered
with a drug like mefloquine and the patient should be advised about the risk.

Describe the chemoprophylaxis of malaria in Sri Lanka

Depending on the malaria risk in the area to be visited, international travelers may also need to take
preventive medication (chemoprophylaxis) prior to, during, and upon return from their travel.

Consultation on preventive chemotherapy must be considered about three weeks before travel.

Travelers and their doctors should be aware that no antimalarial prophylactic regimen gives complete
protection, but good chemoprophylaxis (adherence to the recommended drug regimen) significantly
reduces the risk of fatal disease.

All prophylactic drugs should be taken with unfailing regularity for the entire duration prescribed.
If a traveler develops a severe adverse effect after taking a chemoprophylactic antimalarial drug, he/she
should be advised to stop medication and seek medical advice

An individual who experiences fever a week or more after entering a malarious area should consult a
physician or qualified malaria laboratory immediately to obtain a correct diagnosis and safe and effective
treatment.
The drug used is mefloquine and it is issued by the anti-malaria campaign

Dosage
- 250mg once weekly
- Started one week before entering the endemic area and continued for at least 4 weeks after
leaving the area.

Describe what precautions the soldier should take to protect against malaria. (30 marks)

1) Depending on the malaria risk in the area to be visited, international travelers may also need to
take preventive medication (chemoprophylaxis) prior to, during, and upon return from their
travels.

2) Consultation on preventive chemotherapy must be considered about three weeks before travel.

3) Travelers and their doctors should be aware that no antimalarial prophylactic regimen gives
complete protection, but good chemoprophylaxis (adherence to the recommended drug
regimen) significantly reduces the risk of fatal disease.

4) All prophylactic drugs should be taken with unfailing regularity for the entire duration
prescribed.

5) If a traveler develops a severe adverse effect after taking a chemoprophylactic antimalarial drug,
he/she should be advised to stop medication and seek medical advice

6) An individual who experiences fever a week or more after entering a malarious area should
consult a physician or qualified malaria laboratory immediately to obtain a correct diagnosis and
safe and effective treatment.

7) The drug used is mefloquine and it is issued by the anti-malaria campaign. Dosage is
- 250mg once weekly
 - Started one week before entering the endemic area and continued for at least 4 weeks after
leaving the area.

8) Patient is advised to use mosquito repellents and nets when sleeping in the area

9) He should keep the stays clean so that mosquito breeding places are avoided.

Introduction to Anti Malarial Drugs

Name Action and stages Contraindications Side Other Important Points

Effects

Chloroq Conc in parasitized red cells Ophthalmic examination Retinopat ● Not effective against
uine 1) Inhibits formation of hemozoin if on long term Rx hy or hypnozoites or
- From heme (formed by digestion of maculopat falciparum
RBC) Arrhythmias hy or due
to binding ● Given 3 doses orally
(This step is catalyzed by heme polymerase 1) Myasthenia to skin (10 - 10 - 5)
enzyme) Gravis
2) Psoriasis GIT ● Resistance is
2) Heme accumulates in cell 3) Seizures CVS widespread
4) Porphyria CNS
3) Lyses membrane and leads to death 5) G6PD def Eye
Skin
- PV Hair
PO Hemolysis
PM Schizonts - G6PD

- PV gametocytes

Primaq Useful for a RADICAL CURE of PV PO PM C/I GIT

uine - Pregnancy
- Hypnozoites - Lactation Hematolo
- PF gametocytes - Child < 1y gical
-G6PD def
Not effective against schizonts Caution -Methemo
- G6PD globinemi
 a
-Granulocy
topenia

Coarte C/I GIT Absorption is enhanced by a

m Lumefantrine - Prevents heme detoxification - Pregnancy T1 MSS fatty meal
- Child < 5kg CNS
Arthemeter - Rapidly metabolized free CVS Administered as six doses
radicals Caution Skin
- Drug interaction
Schizonticidal drugs with QT
prolongation

Quinin Mechanism same as chloroquine C/I Metabolic Oral quinine or IV if severe

e - Hemoglobinuria CVS
Schizonticidal drugs - Myasthenia Given in pregnancy
All four species Gravis Heam
- Optic Neuritis (G6PD Monitor blood glucose
Ineffective against hypnozoites - Tinnitus def)
And Falciparum gametocytes
CNS

Tinnitus

Artemis Fast acting schizonticides Well tolerated

inin
Related Artesunate is given IV or IM
Compo Arthemeter is given oral
unds

Mefloq Schizonticidal drugs C/I Neuropsyc

uine Mechanism same as chloroquine - Psychiatric hiatric
Active against PF illnesses
- Convulsions Hypersens
Chemoprophylaxis - Quinine HS itivity

GIT

Management of Malaria

Basis of antimalarial treatment

● Clinical Cure - Kill schizonts
● Radical Cure - Kill hypnozoites (in PF the clinical cure is the radical cure)
● Prevent Transmission - Eliminate gametocytes
 ● Chemoprophylaxis - Destroy schizonts in liver and erythrocytes

Condition Drug Regime

PV Mono Infection 1) Chloroquine

(10 - 10 - 5) mg/kg
For 3 days

2) Primaquine
15mg base
For 14 days

PF Mono Uncomplicated 1) ACT

(weight appropriate)
(never monotherapy)

2) Primaquine
Single dose
0.75 mg/kg

PF Mono Complicated 1) Artesunate IV (first line)

2.4mg/kg on admission

Again at 12 h and 24 h
Then once a day

2) Coartem
Full course
6 days

3) Primaquine
0.75 mg/kg
Single dose

PF Uncomplicated in Children 1) Coartem (first line)

Monitor closely

2) Primaquine
Only if > 1 year

PF + PV Mixed Infection 1) Artemisinin

(weight appropriate)
 2) Primaquine
0.25mg for 14 days

PF in Pregnancy Uncomplicated
● T1 - Oral quinine + Clindamycin
● T2 and T3 Coartem
● Lactating - Coartem

Severe
● T1- IV quinine Until improvement
● T2 and T3 - IV quinine Until improvement
- Coartem After improvement

Avoid Primaquine in pregnancy and lactation (Child < 1y, G6PD)

Avoid Coartem in T1

INTRODUCTORY

Pharmacokinetics and Pharmacodynamics

Describe using appropriate diagrams, what is meant by the therapeutic index of a drug. (30 marks)

Therapeutic index of a drug is the ratio between minimum toxic level and the minimum therapeutic
level.
 Therapeutic index = Minimum toxic level / Minimum therapeutic level (5)

Therapeutic index denotes the margin between therapeutic and toxic doses. (3)

Higher the margin, the safer the drug. (2) Therefore, drugs with high therapeutic indexes are preferred.
(3) If the therapeutic index is low, the drug should be monitored. (4)

Drugs with low therapeutic index include Warfarin, Insulin, Digoxin, Gentamicin, Theophylline (2)

Doses lower than the lower limit of the therapeutic index are referred to as “Subtherapeutic Doses” and
are too low to cause a desired therapeutic effect. Doses higher than the upper limit are considered toxic
and any further increments lead to increasing toxicity with little to no effect on therapeutic benefit.

Therapeutic efficacy is the capacity of a drug to produce an effect and refers to the maximum such effect
(For example amiloride has low efficacy and furosemide has high efficacy when considering renal Na
excretion)
First pass metabolism (15 marks)

First pass metabolism is a process in which drugs are absorbed across the gut wall and delivered to the
liver via portal blood prior to entering into the systemic circulation. (3)

A drug is metabolized in the gut wall, portal blood and mainly by the liver. (2) As a result, only a small
portion of the active drug reaches the systemic circulation and target tissue. Therefore, it reduces the
bioavailability of the drug. (3)

A drug with a high hepatic extraction ratio will have low bioavailability. Morphine is almost completely
absorbed but hepatic extraction is high therefore bioavailability is less.

The first pass metabolism can be bypassed by giving the drug via sublingual, buccal and parenteral
routes. (2) Because they allow drugs to be absorbed directly into the systemic circulation. (1) The drugs
that are administered via oral and rectal routes undergo first pass metabolism. (2) In addition, liver can
excrete the drug into the bile. (1)

Factors that affect drug metabolism are liver disease, liver blood flow, age, genetic and presence of other
drugs.

Dose response curve (15 marks)

PLAN -
Definition
On increasing some flatline and others continue
Curve gives an idea about ”Potency”
Curve gives an idea about ”Therapeutic Index”
Dose response curve is a curve plotting the relationship between the dose of a drug administered and its
pharmacological effect. (2)

The shape of the curve shows the extent to which the desired response alters as the dose is changed. (1)

With increasing dose, some drug responses get increased initially and become flat later. (1)
Eg- Thiazide shows a flat dose response curve. (1)
Some drug responses increase more and more with increasing drug dose (1)
Eg- Furosemide (1)

Drug response curves reveal potency of a drug.

Drugs that are highly potent need only a small drug dose to give rise to a large drug response. (1)
Eg- Same drug response [X] is given by the highly potent drug with a smaller drug dose [A], than
the less potent drug [A<B]. (1)

Drug response curve also reveals the maximum efficacy of drugs. (1)
However, efficacy is considered more highly than potency in clinical settings.
Dose 1 - Drug B has maximum efficacy and maximum potency both.
Dose 2 - Drug A is the most potent drug. Drug B has the maximum efficacy.
(For explaining – 1 mark)

Drug response curves also reveal therapeutic index. (2)

(For explaining in words/graph – 1 marks)

Partial agonist (25 marks)

Binding to and blocking the receptor
Preventing the proper agonist from acting (5)
Also capable of low degree of activation / have minimal agonist action (5).
Therefore, they are called partial agonists.

In clinical situations a partial agonist will act as an antagonist (4).

Oxprenolol, Pindolol, Acebutolol, Esmolol (Any 2 - 3x2 = 6)

Are partial adrenoceptor agonists
Although they block the B receptor
When compared to propranolol, which is pure B agonist
Shows less bradycardia and a lesser fall in CO

Compared to propranolol which is a pure beta antagonist, X (any beta blocker with partial agonist
activity) has partial agonist activity. Therefore, though both drugs block the beta receptor, partial
agonists will show less bradycardia, less fall in cardiac output etc (5).

Competitive antagonism (25 marks)

A drug that inhibits or decreases the action of an agonist is called an antagonist (4).

In competitive antagonism the antagonist acts by binding to its receptor reversibly (5)
and preventing the binding of the natural agonist (5).

Follows the law of mass action

Since natural agonists and antagonists compete to occupy the receptor (3)
When the concentration of the natural agonist increases the antagonist activity will be reduced (2).

Eg - Any beta blocker- Metoprolol / Atenolol etc.

Antimuscarinic drugs- Atropine/ Ipratropium
Competitive alpha 1 blocker - Prazosin (Any 2 drugs 3x2= 6)

Zero order kinetics (25 marks)

As the amount of drug in the body increases (2) the metabolic processes / reactions which have a
limited capacity become saturated (4).
Then the rate of reaction becomes no longer proportionate to the dose / drug concentration in the
body (6). Rate of process reaches a maximum amount and stays constant at that level (5).

Usually, enzyme mediated metabolic reactions are most likely to show zero order kinetics (2).
Eg - Aspirin metabolism
- Enzymatic elimination of phenytoin
- Alcohol metabolism
- Absorption of Fe
- Depot IM formulations or drug implants
(Any 2 - 3x2 = 6)

First order kinetics (25 marks)

Also known as exponential processes

A constant fraction of a drug is transported or metabolized per unit time (5). The rate of absorption,
distribution, metabolism, and excretion of the drug is directly proportional to its concentration in the
body (6).

Most of the drugs follow first order kinetics in clinically used doses(5).
Follows the Law of Mass action

In the elimination phase the time taken for any drug concentration to fall to half its value (Half Life) is
always the same
Eg: Amoxicillin, Desloratadine (3x2=6)

Agonist (15 marks)

Agonist is a drug which acts as a binding ligand to a receptor, stimulating the receptor function. (2+2)
Drug + receptor = response
They resemble the natural ligands of a receptor. [neurotransmitter / hormone] (3)
Eg- Natural: Adrenaline on beta 2 receptors – Bronchodilation
Drugs: Salbutamol on beta 2 receptors – Bronchodilation
(Marks; drug – 1, correct receptor – 2, action - 1)

But agonists are more resistant to degradation than natural agonists. (2)
Also, their action is longer than the natural substance they mimic. (2)
Eg- Salbutamol causes bronchodilation for a longer period.

Antagonist (30 marks)

Antagonist is a drug that decreases / inhibits the action of an agonist. (4)
It prevents binding of the agonist to the receptor site.
Therefore, it decreases the action of the receptor. (2)
Eg- Propranolol blocks beta 1 and beta 2 receptors which are stimulated by Adrenaline.
(Drug- 2 + correct receptor = 2)

There are 3 types.

1) Competitive antagonist- (2)
Compete with agonists to bind with the receptor. There, mostly drugs bind with the receptor reversibly.
(2)
Eg- Propranolol (2)

2) Non-competitive antagonist- (2)

Irreversible binding of a drug blocks binding of agonist with the receptor. (2)
Eg- Aspirin inhibits COX1 pathway by irreversibly binding to the receptor. (2)

3) Physiological antagonist- (2)

These do not act at receptor level. They inhibit the receptor action by acting in a peripheral site. They do
not have anything to do with the receptor. (4)
Eg- Action of adrenaline in anaphylaxis. (2)
 4) Inverse antagonists (2)
Have an action specifically opposed to the agonist
Eg- Benzodiazepines and B carbolines

Volume of distribution of a drug. (20 marks)

Volume of distribution is the volume in which it appears to distribute if the concentration throughout
the body were equal to that in plasma. (4)
Vd = Dose/Concentration (2)
There are factors affecting Vd.

If a drug is more water soluble, its plasma concentration will be high. Therefore, its Vd becomes small.
E.g : Water soluble drugs – Gentamicin

If a drug is more plasma protein binding or less tissue binding, its Vd becomes small.
E.g.: Warfarin
(Give 2 marks for above any point, with 1 mark for an example.)

If the drug is more tissue binding, its plasma concentration will be low. Therefore, its Vd becomes large.
(2)
E.g - Digoxin – Binds to Na/K ATPase pump. (1)

More lipid soluble drugs also have large Vd. (2)

Half-life of a drug is depended on Vd. (2)
t1/2 = 0.7 * Vd/Clearance

It is useful in determining drug frequency.

Loading dose can be calculated using Vd. (2)

Loading dose = Concentration * Vd/ Bioavailability

Drugs which have large Vd can not be removed by hemodialysis because their concentration is low in
plasma. (2)

Tolerance (20 marks)

Tolerance is the decreased responsiveness to a drug brought on by previous exposure. (4)

The dose must be increased to get the previously obtained response

There are 3 types

1. Pharmacological tolerance (2)
2. Physiological tolerance (2)
3. Metabolic tolerance (2)

1) Pharmacological Tolerance

This occurs due to pharmacological reaction of drugs on the target. (1)

Eg - 1) Organic nitrates used in angina treatment.
There, Nitrates are converted to NO which is a vasodilator by Glutathione. With the depletion of
Glutathione stores, this conversion won’t happen. Therefore, there should be Nitrate free
intervals at night to replenish Glutathione stores.

Eg - 2) Opiates With time opiates cause its receptor down regulation.

Therefore, to get the same response, opiate concentration has to increase with time.
(For any example, 2 marks)

Eg - 3) Ephedrine acts by causing release of stored noradrenaline from nerve endings. With
prolonged use noradrenaline stores are decreased.

2) Physiological Tolerance
Happens due to homeostasis (1)
 Eg - Diuretics used for antihypertensive effects also causes RAAS system activation.
Therefore, the antihypertensive effect is blunted (2)

3) Metabolic Tolerance
Happens due to increased metabolism (1)
Eg - Rifampicin is a cytochrome p450 enzyme inducer. Warfarin is metabolized by cytochrome
p450 enzymes in the liver. Concomitant administration of both drugs causes reduction in the
anticoagulant effect of Warfarin. (3)

Define Plasma Elimination Half-life of a drug(10 marks)

Briefly Explain 2 Clinical Uses Of The Above(20 marks)
Explain how renal failure affects the half-life of gentamicin(10 marks)
Describe how the dose of gentamicin is adjusted inpatient with renal impairment(10 marks)

Plasma Elimination Half-life of a drug - The time it takes for plasma concentration or the amount of drug
in the body to be reduced by 50%.

Clinical Uses Of Plasma Half Life

A) To Determine the time required to reach steady state after starting a drug

When A drug is given at a constant rate (continuous repeated administration),time to reach steady state
depends only on 1/2.

After 5t1/2periods theamountof druginthe bodyisconstant and the plasma concentration is at a plateau.

By Knowing the half-life time to reach steady state concentration can be calculated.

B) To Determine The Drug Concentration

After Discontinuing A Drug, the plasma concentration would fall to virtually zero in 5t1/2 periods.
Therefore,t1/2 can be used to determine when the effect of certain drugs would be lost in a patient.

C) To Determine Dosing Frequency

By Knowing Elimination T1/2,it would be used to determine the dosing frequency in order to maintain
the drug at the required plasma level.

Effect of renal failure on the half-life of gentamicin

Renal Failure is a condition in which the kidneys lose their functional ability.
Gentamicin is an aminoglycoside which is excreted unchanged by renal glomerular filtration.

Clearance of drug is the volume of plasma completely cleared of drug per unit time.

In Renal failure clearance of gentamicin is less.

Elimination Half-life is inversely proportional to plasma clearance.

Half-life=0.7Vd/clearance

Therefore,when the clearance is less,plasma half-life gentamicin increases.

Therefore,renal failure causes half-life gentamicin to be increased.

Dose adjustment of gentamicin in renal failure patient

In Renal Failure Elimination Half-life of gentamicin increases.

Therefore, the effect of gentamicin in the body lasts for a long period of time.

In order to reduce toxicity caused by gentamicin maintenance dose which depends on renal clearance is
decreased.

Rate Of Administration = Rate Of Elimination At Steady State Conc

Creatinine clearance of patients is measured.
Maintenance dose is reduced to match the drop in creatinine clearance.

Short note on Drugs acting on receptors (25 marks)

Receptors are proteins on either cell surface or cell interior which bind to molecules known as ligands.
Drugs act as ligands.

When bound proteins undergo a conformational change which in turn induces changes in systems
intracellularly that bring about response to the drug.

Drugs could act as,

Agonists
● Drugs bind to the receptor and stimulate the cell's response.
Eg- Adrenaline(drug) interacts with β1 receptor and causes tachycardia
● Agonists resemble natural agonists but they have greater capacity to resist degradation; they act
longer.
Antagonists
● They inhibit or decrease the action of antagonists.
● This prevents binding of an agonist to the receptor and exerting its effect.
Eg- Propranolol is a β1and β2 receptor blocker and prevents adrenaline (agonist) action
on β1 and β2 receptors.
Partial Agonist
● Drugs that have only minimal agonist action and binds to receptors and prevents proper agonists
from acting.
● Therefore,in clinical situations this actually acts as an antagonist.
Eg - Oxprenalol and pindolol act as β adrenoceptor partial agonists.

With long term use of drugs may lead to increase in number of receptors (up- regulation) or decrease in
the number of receptors (downregulation)
Certain drugs are more selective to one subtype of receptors than others.These drugs have less severe
side effects.

But at higher doses this effect is lost.

Drug Interactions

Inducers and Inhibitors of Hepatic Enzymes

Hepatic enzymes affect drugs in several ways.

Many drugs go through hepatic metabolism which inactivates the

drug,thus rendering it less bioavailable.

Some drugs get activated in the liver.

Main enzyme system responsible is the P450 enzyme system.

Substrates of hepatic enzyme system
Eg - Warfarin
Hepatic enzyme inducers and inhibitors affect the plasma levels of drugs which are substrates for hepatic
enzymes.

Enzyme Induction
Extent of enzyme induction depends on the drug and dose.

Maximal effects usually occur after 7-14 days and require an equal or longer time to dissipate after the
enzyme inducer is stopped.

Therefore,enzyme induction interactions are of delayed onset slow resolve.

● Barbiturates
● Carbamazepine
 ● Rifampicin
● Efavirenz
● St. John's Wort
● Phenytoin
● Griseofulvin

If rifampicin and warfarin is given to a patient at the sametime rifampicin would induce hepatic
enzymes.Since it is a hepatic enzyme inducer more Warfarin (a substrate of hepatic enzymes) would get
metabolized.

Therefore, the anticoagulant effect of warfarin would be less.

Enzyme Inhibitors
Drugs That Inhibit Hepatic Enzymes.
Can occur within 2-3 days resulting in rapid development toxicity.
● Amiodarone
● Isoniazid
● Ciprofloxacin
● Clarithromycin
● Erythromycin
● Fluconazole
● Ketoconazole
● Metronidazole
● Omeprazole
● Verapamil
● Paroxetine

If a patient on warfarin is given isoniazid hepatic enzyme inhibition occurs resulting in less enzyme
inhibition.Plasma warfarin levels would increase. Effect of warfarin would increase resulting in
spontaneous bleeding developing in the patient.
Using your knowledge on pharmacokinetics explain why drugs Low therapeutic index are more likely
to develop clinically significant drug interactions (20 marks)

Therapeutic index of a drug is the maximum tolerated dose divided by minimum curative dose is termed
as therapeutic index.

This denotes the margin between therapeutic and toxic doses.

Drugs With Low Therapeutic Index
● Warfarin Digoxin
Drugs With High Therapeutic Index
● NSAIDS
● Sedatives/hypnotics (Benzodiazepine)

Drugs having low therapeutic index are more likely to develop clinically significant drug interactions
If the response of one drug isalteredbyadministeredby administration of the second drug, a drug-drug
interaction is said to have occurred.

Drug Interactions Are Of Three Types.

Pharmacodynamics Interactions
Pharmacokinetic Interactions
Pharmaceutical Interactions

Pharmacokinetic interactions alter the concentration of the drug that reaches its site
Of action due to effects on absorption,distribution,metabolism and excretion.

In drugs with narrow therapeutic index thereisonly asmallmargin exists between therapeutic and toxic
doses Due to this,small quantitative change at the target site(receptor or enzyme) would lead to
substantial changes in effect. This would give rise to unwanted side effects at very small dosage changes.

Therefore,drugs with low therapeutic index would result in clinically significant drug interactions.
List the drugs that can cause interactions in the above prescription (15 marks)

Erythromycin - Theophylline (Enzyme Inhibitor-Theophylline toxicity)

Atenolol - Diazepam (Enhanced hypotensive effect)
Prednisolone - Diazepam (Low excretion rate of Diazepam)
Prednisolone - Theophylline (Theophylline toxicity and hypokalemia)
Diazepam - Erythromycin (Diazepam toxicity)

List 3 medicines that should be omitted or replaced, giving reasons (25 marks)
1. Theophylline should be removed (3)
Theophylline is a bronchodilator with a narrow therapeutic index. (2)
It is also metabolized by the CYP450 system, therefore prone for drug interactions. (2)

It is usually not needed for stage 3 chronic asthma unless other bronchodilators are ineffective
and unavailable. (2)

2. Prednisolone can be replaced by an inhaled corticosteroid (3)

In stage 3 chronic asthma systemic corticosteroids are not given. They are
usually used for acute severe asthma. (2) So we can combine Salmeterol with am ICS like
Beclomethasone/ Budesonide (2)

3. Atenolol can be replaced with a Calcium channel blocker (3)

Atenolol is a beta 1 receptor blocker but will lose selectivity at higher doses and will cause beta 2
receptor blockage too (In bronchial smooth muscles). (2)
This will give rise to bronchoconstriction. (2)
CaCB will not have an effect on the respiratory system. (2)

4. Diazepam is not needed in this patient. It is a benzodiazepine used as an anxiolytic/

anticonvulsant/ muscle relaxant/ sedative. Not an indication for asthma.
 5. Erythromycin is a macrolide given mainly for pertussis. Not an indication for asthma

Main- first 3 points. If 4 and 5 are also written give marks accordingly

Explain the reason for reduced oral bioavailability of Digoxin, when administered together with
Rifampicin

Bioavailability of a drug is the fraction of unchanged drug reaching the systemic circulation following
administration by any route

When the drug is given in oral route bioavailability mainly depends on degree of absorption by the GI
tract and amount of drug metabolized and eliminated before entering the systemic circulation which is
also known as first pass metabolism

When the digoxin is given with rifampicin, mainly GI absorption is interfered reducing the bioavailability
of digoxin since digoxin doesn’t undergo considerable first pass metabolism

Digoxin is a substance of P glycoproteins

- Found on reverse transporters present in GI mucosa
- Also present in proximal tubule of nephron, adrenal gland, ducts of pancreas
- Blood-brain barrier in a healthy individual

These channels cause to pump back its substance into the gut lumen
Rifampicin is an inducer of P glycoproteins

Therefore, rifampicin accelerates the action of p glycoproteins and reduces the enteric absorption of
digoxin by pumping absorbed digoxin back into the lumen

Therefore, the amount of digoxin presented to the systemic circulation is significantly reduced when
digoxin is co administered with Rifampicin orally

List two drugs that act as inhibitors of P glycoproteins

 ● Amiodarone
● Clarithromycin
● Erythromycin
● Ketoconazole
● Ritonavir
● Quinidine

Oral contraceptive failure with Rifampicin. (25 marks)

Metabolism of drugs mainly happens in the liver by cytochrome p450 enzyme complex. (2)

This cytochrome complex can also be induced or inhibited by some other drugs. (2)
Therefore, this inducing or inhibiting drugs can alter the cytochrome related drug metabolism. (2)

Oral contraceptive drugs are used for the contraceptive purposes, by

increasing estrogen and progesterone concentrations in the body. (2)

They are normally metabolized by the hepatic cytochrome p450 enzyme complex into inactive
substances. (4)

Rifampicin is an antimycobacterial drug.

It acts as an inducer of hepatic cytochrome p450 complex. (4)

When taking oral contraceptive pills with Rifampicin, Rifampicin induces

hepatic cytochrome system. Therefore, the metabolism of oral contraceptive drugs has increased. (4)

Due to that, their hormones are broken down at a high rate and get
inactivated. Therefore, contraceptive hormone levels in the body are reduced and clearance gets
increased. The contraceptive effectiveness fails. (4)

Because of that, when taking rifampicin and oral contraceptives together, there should be a second
method in order to gain contraceptive protection. (1)
Theophylline toxicity with Erythromycin. (25 marks)

Metabolism of drugs mainly happens in the liver by cytochrome p450 enzyme complex. (2)

This cytochrome complex can also be induced or inhibited by some other drugs. (2)

Therefore, this inducing or inhibiting drugs can alter the cytochrome related drug metabolism. (1)

Theophylline is a drug used in the treatment of asthma and COPD in order to cause bronchodilation. (2)
It gets metabolized by hepatic cytochrome p450 complex. (3)
It has a low therapeutic index. (2)

Therefore, a slight increase in the drug concentration can move up to the toxic levels causing
theophylline toxicity. (1)

Erythromycin is a macrolide, acting by inhibiting 50s subunit of bacterial ribosomes. (2)

It is a drug which acts as an inhibitor of hepatic cytochrome p450 complex. (3)

When these 2 drugs are administered together, erythromycin inhibit cytochrome system and arrest the
metabolism of theophylline. (3)

Therefore, theophylline concentration in the body gets increased. Its clearance gets reduced. (2)

Due to the raised drug concentration, theophylline toxicity arises in the body (1) and causes nausea,
vomiting, diarrhea, insomnia and palpitations like symptoms. (1)

Compare type A and type B adverse drug reactions. (10 marks)

Type A ADR
1) Are augmented reactions.
 2) Occurs in anyone.
3) Pharmacodynamic effects.
4) Predictable from the pharmacology of the drug
5) Result from an excess of normal, predictable, dose-related, and pharmacodynamic
effects of the drug
6) Skill management is needed to reduce the incident.

Eg - Hypoglycemia, Hypertension

Type B ADR
1) Are bizarre reactions.
2) Occurs in some people.
3) Not due to normal pharmacology of drugs.
4) Predictable or Unpredictable.
5) Happens due to unusual attributes of the patient interacting with the drug. Not dose related.
6) Skill management is needed to reduce the incident. (Drug fatalities)
Eg - Anaphylaxis with penicillin
(For any 4 points (From 1-6) – 8 marks, with 2 marks for examples on each side.)

Explain giving an example why drugs with zero order kinetics are more likely to develop clinically
important drug interactions (30 marks)

In zero order kinetics the amount of drug in the body raises,the metabolic reactions or processes that
have limited capacity become saturated. The process reaches a maximum amount which stays constant.

If the response of one drug is altered by administering a second drug, a drug-drug interaction is said to
have occurred.

Outcomes of clinical importance in drug interactions could be,

Harmful due to,
- Increased Toxicity
- Decreased Efficacy
Beneficial Due To Increased Activity.
Or it could have no clinical significance

Drug Interactions Could Occur Due To Three Mechanisms.

- Pharmacodynamic
- Pharmacokinetic
- Pharmaceutical

Pharmacokinetic interactions result in alteration of the concentration of the drug that reaches its site of
action due to effects on absorption, distribution, metabolism and excretion.

This mechanism of action may lead to alterations at the level of metabolism of the drugs with a saturable
process.

Even small changes at this level would lead to saturation of enzyme systems,thus resulting In
considerable large alterations of the drug's plasma concentration.

Alteration of plasma concentration would alter the pharmacological effect of the drugs as well as the
side effect profile.

Therefore,drugs with zero order kinetics are more likely to develop clinically important drug interactions.

Write a short note on drug interactions (Just read this but not too much)

Pharmacodynamic drug interactions -

● One drug causes a change in patient response to another drug without altering that drug’s
pharmacokinetics
● Both drugs act on the target site of clinical effect exerting synergism or antagonism
● Drugs with opposing pharmacological effects (competitive antagonism and physiological
antagonism) may reduce the response to one or both drugs
● Synergism could be potentiation (2+2=5)
Or addition (2+2=4)
Pharmacokinetic drug interactions -

Alteration of the concentration of the drug that reaches its site of action by effects on
a) Absorption
Direct chemical interaction
● Al and Mg in antacids form insoluble complexes with tetracycline
● Ca reduces absorption of tetracyclines
● Cholestyramine - levothyroxine, digoxin, warfarin
Altering gut motility
● Reduction of mobility by analgesics, TCA antidepressants
● Purgative - Steroids and digoxin are poorly absorbed
Altering gut flora
● Antimicrobials potentiate the anticoagulants by reducing bacterial production of Vit K
● Affects transport proteins such as P - Glycoproteins and organic ion transporters
Any other interactions
● Vasoconstrictors delay the absorption of local anesthetic

b) Drug distribution
- Competition for plasma protein binding
- Displacement from tissue binding sites
- Alterations in local tissue barriers (P glycoprotein and BBB)

c) Metabolism - Enzyme induction and activation

- And due to hemodynamic effects - Propranolol (reduces the cardiac output) and
lidocaine (extensive hepatic metabolism)

d) Excretion - Renal excretion of drugs that are weak acids or weak bases may be influenced by
other drugs that affect urinary pH
- Inhibition of active tubular secretion of drugs (P glycoproteins)

Pharmaceutical interactions

Interactions that occur prior to systemic administration.

Eg - Incompatibility between two drugs mixed in an IV fluid
Phenytoin in dextrose
Beta lactam antibiotics and gentamicin

Using your knowledge on pharmacokinetics of drugs, explain why phenytoin toxicity can occur in a
patient with Chronic liver Disease (20 marks)

Phenytoin can be found in two forms in an equilibrium in the plasma

Free form (1)
And Plasma proteins bound (1)

Free form of phenytoin exerts its therapeutic effect and adverse effects including toxic effects (2)
Most of the phenytoin found in plasma is in protein bound form / highly protein bound (2) (around 91%)

And also, phenytoin has a narrow therapeutic index (3)

When a drug has a narrow therapeutic index small change in plasma concentration leads to
concentration dependent adverse effects (1)

Therefore, any insult occurs to the bound fraction of phenytoin causes phenytoin toxicity easily by
increasing free plasma drug concentration (2)

In chronic liver disease synthetic function of the liver is reduced (1) resulting in hypoproteinemia.
Therefore in CLCDs phenytoin binding proteins mainly albumin(1) significantly reduced in plasma (2)

When the plasma protein binding capacity reduces free form of phenytoin increases in the plasma in
chronic liver diseases resulting toxicity (2)

If phenytoin is indicated in a patient having a chronic liver disease trough monitoring of plasma
concentration is mandatory (2)

Other Intro SEQs

Explain the following statement: ‘It is necessary to be cautious when drugs that are metabolized by
liver, are administered to neonates’ (40 marks)

Neonate is one month old.

● He has a high body water percentage (70-75%) and (1)
● Low body fat percentage (15%). (1)
This should be considered when selecting the type and dose of drugs.

● Drug binding plasma protein levels are low in neonates. (3)

- Decreases the drug amount which is delivered for hepatic metabolism
- And Renal clearance. (2)
- Can increase the unbound drug concentration in neonates causing drug toxicity. (2)

Drug metabolism normally happens in the liver with the aid of cytochrome p450 enzyme complex and
conjugating enzymes. (3)
● Lower concentrations in neonates than in adults. (3)

- Drug metabolism in the liver happens at a slow rate. (2)

- Clearance rate will also be slow. (1)
- Eliminating half-life will be prolonged. (1)

These drugs will accumulate in a high concentration in the neonatal body for a longer period of time
than in adults. (2) This should be considered when calculating therapeutic dose, drug intervals and
therapeutic efficacy of and dose should be reduced in order to prevent drug toxicity. (1)

Most hepatic metabolizing drugs have a renal clearance. (1)

● But neonatal kidneys are also not matured yet. (3)
- Drug’s renal clearance also takes a longer (2)
Also consider this (1)
● Mothers may take drugs that induce early hepatic enzyme maturation in neonates. (3)
Eg- Phenobarbital (1)
- Rate of hepatic drug metabolism will be increased. (3)
- Duration of free drug concentration available in the body will be decreased. (1)
 - Renal clearance will therefore increase (1)

Considered when calculating a dose of a hepatic metabolizing drug to have the same therapeutic effect
as the neonate whose hepatic enzymes are still immature. (1)

Explain the pharmacological basis of giving IV NaHCO3 in Aspirin poisoning (25 marks)

PLAN
- Properties of normal aspirin
- Metabolism into Salicylic Acid
- Inactivation of Salicylic Acid
● At low doses - No problems
● At high doses - Accumulation in blood
- Why it can’t be removed from renal tubules
- NaHCO3 added to renal tubules
- Salicylic acid ionized and is removed

Aspirin is a
- Lipid soluble drug
- Absorbed from the stomach and upper GI (1)
- It is a weak electrolyte
- SO it can ionize according to the environmental pH (1)

It is metabolized by the liver

- To active form (Salicylic Acid) with a pKA of 3 (1)
- At neutral ph (7.4) of blood
- It highly ionizes (3)

Ionized drugs are

- Lipid insoluble
- Non diffusible (2)
So it remains in the ECF
Until it is excreted by the kidney (1)

Usually, Salicylate ions are inactivated in the liver (by conjugation) with glycine (1)
At LOW doses
- this process occurs normally
- And follows first order kinetics (1)
At HIGH doses (such as in aspirin overdose)
- It follows ZERO order kinetics
- And saturation of the process occurs
- Accumulation of salicylic acid in the psalms
- Metabolic acidosis (1)

The treatment must aim to remove salicylic acid from plasma

- By enhancing it’s renal excretion (1)
But this would be problematic as tubular fluid is more acidic compared to the plasma
- Most salicylate ions become unionized and lipid soluble in the tubular fluid
- This leads to enhanced reabsorption of salicylate acid back into the circulation (2)
- Further increasing salicylic acid levels in the plasma

This challenge can be overcome by alkalizing the urine (2)

- IV sodium bicarbonate is an alkalizing agent (1)
- Which alkalized renal tubular filtrate
- By neutralizing H ions of the filtrate (2)
Leading to
- An alkaline medium in the renal tubules
- In which salicylic acid can become ionized
- And water soluble (2)
- Reducing tubular reabsorption and excretion via kidneys (1)
Describe the following giving one example for each
A) Systemic therapy (10 marks)
Any treatment that affects the entire body or an entire organ system
Eg : I/V Gentamicin,
B) Topical therapy (10 marks)
A treatment that acts locally on the site of administration
Eg : Salbutamol Inhalers, Steroid Inhalers

List the advantages and disadvantages of topical therapy compared to systemic therapy (20 marks)

Advantages
Provision of high local concentration usually without systemic effects
Plasma drug concentration does not need to be monitored
Able to by-pass 1st pass metabolism

Disadvantage
Absorption can occur, especially when there is tissue destruction so that systemic effects result, e.g.,
adrenal corticosteroids and neomycin to the skin, atropine to the eye.
Sometimes erratic absorption may occur.
Usually does not render immediate action and may be less effective for generalized disorders

Pyridostigmine is effective in the treatment of myasthenia gravis. (40 marks)

Myasthenia gravis is an autoimmune disorder. (3)

Autoantibodies are produced and bind to the nicotinic (3) acetylcholine receptors at NMJ. (2)
Causes downregulation of receptors by internalization and degradation. (3)

In a normal person
- Repetitive stimulation at the NMJ cause a decline in number of Ach molecules
- Causing receptor upregulation. (2)
In myasthenia gravis with repetitive stimulation
- Decline in Ach molecules at NMJ with no receptor upregulation. (3)
It impairs transmission of impulses across the NMJ. (2)
Leads to loss of function at NMJ causing muscle weakness and easy fatigability. (2)

Pyridostigmine
- Indirectly acting
- Medium duration (3)
- Anticholinesterase. (2)
- Reversible action. (3)
- Prevents breakdown of Ach by acetylcholinesterase. (3)

Therefore, it increases the amount of acetylcholine at NMJ. (2)

Then Ach competes with autoantibodies. (2)
When Ach concentration is increased in the synaptic cleft, it binds with nicotinic receptors and relieves
symptoms of myasthenia gravis. (2)

Therefore, pyridostigmine is used to treat the nicotinic symptoms of myasthenia gravis. (1)
Eg - Reversing respiratory failure (1) (one mark for any symptom)

(Preferred to neostigmine due to - Smoother action and less frequent dosage)\

EXTRA - Differentiating a Myasthenic Crisis from a Cholinergic Crisis
Edrophonium ( A short acting acetylcholinesterase) is given.
Symptoms resolve = Myasthenic Crisis
Symptoms worsen = Cholinergic Crisis

Salbutamol is indicated in the treatment of hyperkalemia (10 marks)

Hyperkalemia is a potentially lethal condition that may cause cardiac arrhythmias, cardiac arrest, or
death.

Salbutamol is a short acting selective β2 adrenergic agonist drug that stimulates the Na/K ATPase pump
on the cellular plasma membranes.
Na/K ATPase pumps actively promote influx of 2K+ into the cell and efflux of 3Na+ out of the cell.
Shifts excess K+ in plasma into the intracellular compartment, correcting the plasma K+ ion
concentration in hyperkalemia.

CVS MODULE
ACEI in HTN and HF

Briefly describe the pharmacological basis of the use of ACE inhibitors in Hypertension (40 marks)

PLAN
- Definition of hypertension
- Formulas in full
- A2 is a vasoconstrictor. Stopped.
- Reduces aldosterone secretion
- Prevents bradykinin breakdown
- Prevents direct sympathetic activation
- Other functions and benefits over other drugs

Hypertension is the sustained elevation of Blood pressure more than 140/90 mmhg for a person’s age
and sex.

BP = CO x TPR (use the full form)

CO = SV x HR

ACEI inhibits the conversion of Angiotensin I to Angiotensin II, thus halting the RAAS pathway

1) Angiotensin II is a potent vasoconstrictor, so its inhibition by ACEI causes vasodilatation.

2) It also prevents the breakdown of bradykinin which is a vasodilator (that act via NO)
Decreases total peripheral resistance.
3) Inhibits aldosterone production by adrenal cortex
 Reduces salt and water retention
Reduced intravascular volume
Reduces preload
Reduced Stroke Volume
4) Prevents Angiotensin II activating the sympathetic system
Reduces circulating catecholamines
Reduces Heart Rate

Additionally

5) Angiotensin II also causes ADH secretion

6) And activation of the thirst center
Results in increased intravascular volume and stroke volume
7) Alters formation and degradation of other vasoactive substances (Substance P)
8) In chronic HTN reduce the risk of cardiac remodeling and hypertrophy

Lowers arterial pressure reduces afterload

Lowers venous pressure reduces preload
Lowers both SBP and DBP

Therefore, ACEI decreases the CO and TPR and thereby is used to reduce the BP.

Other points
- ACEIs are effective for all stages of HTN
- Improved general wellbeing
- No precipitation of CCF, bronchospasms, PVD, bradycardia.
- Absence of metabolic side effects

Reduce HTN induced glomerular damage

At the routine clinic visit a 58 year old woman with diabetes complains of progressively
worsening shortness of breath on moderate exertion and bilateral ankle oedema for 3 weeks. After
evaluation a diagnosis of congestive cardiac failure is made.The following drugs are added to her
prescription. Furosemide 40 mg BDEnalapril 5mg daily

Describe the pharmacological basis for the use of enalapril in this patient. (40 marks)

PLAN
- Basis of ACEI and HF
- (said in previous qn) - Vasoconstriction + Aldosterone production + Sympathetic activation
- Cardiac remodeling + Prognostic benefit

Heart failure is any progressive abnormality that impairs the ventricle’s ability to fill with or eject blood.
ACEI acts on the angiotensin converting enzyme in the kidneys of the RAAS it inhibits the conversion of
inert Angiotensin I to potent vasoconstrictor Angiotensin II, and prevents its action on AT2 receptors.
This provides both symptomatic and survival benefits.

1) Inhibition of vasoconstriction by angiotensin 2

Vasodilation
Reduced TPR
Reduced afterload

2) Inhibits aldosterone production by kidneys

Due to absence of Angiotensin II
Inhibits sodium and water retention
Reducing blood volume
Reducing preload.

3) ACEI reduces sympathetic action on beta receptors

Reducing levels of circulating catecholamines
Doesn’t let heart rate increase in response to excessive diuretics
Increases diastolic filling time
 Increases myocardial perfusion and oxygen supply.

These three facts thus provide symptomatic benefit as well

4) Benefit of inhibiting cardiac remodeling

Preventing further destruction and fibrosis of the heart which usually worsens heart failure
which is stimulated by Angiotensin II.

This is the most important reason to produce prognostic benefits in the long term.

Reduces mortality in patients with both symptomatic and asymptomatic HF

Usually recommended as first line therapy

ACEIs should not be given together with ARBs in heart failure because of the risk of
renal dysfunction and hyperkalemia and no added prognostic benefit when combined.

EXTRA - Other drugs that should be avoided in HF

1) Thiazolidinediones (Glitazones)
2) Calcium Channel Blockers (Amlodipine and Felodipine)
3) Beta Blockers (Except Carvedilol, Metoprolol, Bisoprolol)
4) NSAIDs and COX-2 inhibitors (Cause Na and water retention that worsens HF)

List five parameters that need to be monitored with regard to drug therapy in this patient. (15 marks)
1. Blood pressure
2. Serum electrolytes
3. Blood glucose
4. Renal function

Name two other medications that would benefit this patient with congestive cardiac failure. (10
marks)
1. Spironolactone
2. Beta blockers(carvedilol, metoprolol, bisoprolol)(18th Batch Repeat)
Explain how therapy with ACEI reduces the morbidity following acute myocardial infarction. (30
marks)

ACEI inhibits renin angiotensin aldosterone system

1. Dilated veins and arteries reduce arterial pressure, afterload and preload on the heart which
leads to reduced O2 consumption and workload of the heart.
2. Promote sodium and water excretion resulting in reduced venous return to the heart, reducing
preload.
3. Downregulate sympathetic adrenergic activity reducing level of catecholamines, causing
increased diastolic filling time and thus increases myocardial perfusion and oxygen supply
4. Inhibit cardiac and vascular remodeling associated with MI

Occurrence of a dry cough with enalapril but not with losartan. (30 marks)

Enalapril is an angiotensin converting enzyme (ACEI) inhibitor and Losartan is a Angiotensin II receptor
blocker (ARB).

Both of these drugs are given in heart diseases and as a first line drug in hypertension to reduce blood
volume in order to minimize cardiovascular events.

ACEI inhibits the angiotensin converting enzyme, and thereby prevents conversion of angiotensin I to
angiotensin II, inhibiting the renin angiotensin aldosterone system reducing fluid retention.

Angiotensin converting enzyme (ACE) breaks down bradykinin.

When ACE is inhibited by ACEI, bradykinin tends to accumulate in the upper respiratory tract causing a
dry cough.

ARB acts by inhibiting the angiotensin II receptors thereby reducing vasoconstriction.

It does not inhibit bradykinin breakdown, therefore bradykinin is not accumulated in the upper
respiratory tract and does not cause coughing.

A 45 year old man with diabetes is referred to the medical clinic with confirmed hypertension (BP
160/100mmHg)

What groups of drugs can be used to manage hypertension

ACE inhibitors or ARB
Diuretics
Beta Blockers.
Calcium Channel blockers

Describe the mechanism of action of drugs mentioned above in relation to the pathophysiology of
hypertension

Hypertension is an elevation of blood pressure over the normal level. The blood pressure is dependent
on the cardiac output and the peripheral resistance. Therefore the drug targets should be to reduce the
cardiac output and the peripheral resistance. Blood pressure = Cardiac Output x Peripheral Resistance

Ace Inhibitors
- First line drug in hypertension.
- Inhibit ACE which converts angiotensin I to angiotensin II (vasoconstrictor) and breakdown
bradykinin (vasodilator)
- Peripheral resistance will be reduced.
- Prevent salt and water retention
- Reduces the progression of diabetic nephropathy

ARBs

- Does not inhibit the conversion of angiotensin I to angiotensin II

- Blocks the receptors that are stimulated by angiotensin II preventing its action.
- Lacks the action of prevention of the breakdown of bradykinin.
Therefore the side effects of the bradykinin are also avoided such as cough.

Beta Blockers

- Reducing the contractility and the rate of the heart, blocking the β1 receptors.
- Reduce the atrio-ventricular conduction of the heart and
- Cause adrenoceptor blockage in the atrioventricular system.
- Reduce the renin secretion and increase ANP secretion.

Reduced renin secretion reduces the water retention and elevated ANP increases renal sodium secretion
thereby increasing the water secretion in the kidney.

Therefore, due to above mechanisms the cardiac output is reduced reducing the blood pressure.

Calcium Channel Blockers

Ca2+ is involved in mainly three mechanisms in cardiovascular system

1. Initiation of vascular smooth muscle contraction
2. Initiation of cardiac muscle contraction
3. Functioning of cardiac pacemaker cells and conduction tissue.

It is Ca2+ channels which enters calcium into cells once activated.

Calcium channel blockers blocks L-type calcium channels in
1. Vascular smooth muscles
2. Cardiac myocytes
3. Pacemaker cells and conduction cells.

Therefore calcium channel blocker reduces peripheral vascular resistance and the cardiac output by
reducing both contractility by acting on myocytes and reducing heart rate by acting on AV and SA nodes
(pacemaker cells)

5.3. Out of the drug groups mentioned above, which drugs would you select to manage this patient?
Give reasons.
ACE inhibitors
ACE inhibitors have an extra benefit in diabetes nephropathy reducing albuminuria
(ACE is best used to relieve symptoms).
As this patient is diabetic this drug will be beneficial.

A 60 years old man is admitted with Shortness of breath on excretion. On examination he has bilateral
fine crepitation in the chest and pitting edema in the legs. A diagnosis of congestive cardiac failure is
made. What are the drugs you would use for

Symptom relief

● Thiazide diuretics / Loop diuretic (Given only if the patient is having oedema)
● ACEI/ ARB
● Spironolactone (if not tolerated change to Eplerenone as it does not cause gynecomastia)
● Beta blocker
● Ivabradine (If heart rate is elevated)
● Vasodilators – ISDN, Hydralazine, Digoxin

Long term management of this patient

● ACEI
● ARB
● Beta blockers
● Spironolactone

● Extra - Digoxin has no survival benefit

Describe the pharmacological basis for the use of the above drugs.

ACEI / ARB
- Primary treatment of heart failure
 - They can be used in all stages of chronic heart failure to prevent further deterioration and
progression of heart disease.
- They also help in cardiac remodeling prolonging life in heart failure

Beta Blockers
- Only given to symptomatic patients
- Reduces cardiac workload by reducing HR and CO
- Reduce further worsening of the cardiac condition.
- Bisapralol, Metoprolol, Carvedilol can be used in stable heart failure and left ventricular systolic
dysfunction.
- Start low go slow
- Don’t stop abruptly

Spironolactone
- K sparing diuretic (aldosterone antagonist)
- Acts on distal convoluted tubules
- Inhibits water and sodium retention and potassium secretion.
- Reduce oedema and give symptomatic benefits.
- Due to reduction in pulmonary oedema reduce further worsening of heart failure.
- Considered for patients with severe heart failure who are already receiving an ACEI and diuretic.
- Low dose spironolactone reduces mortality and prolongs life.
- Close monitoring of serum creatinine and potassium

What precautions would you take in the use of the above drugs ?

ACEI / ARB – Previous history of usage causing dry cough , Hyperkalemia, Avoid in PVD
Beta blockers – Asthma, Heart Block, Hypoglycaemia, Slow Withdrawal
Spironolactone – Hyperkalemia, Serum creatinine

Antihypertensive Drugs

Drug Class Indications Contraindications Important Points

Diuretics Gout Thiazides have a flat dose
Systolic HTN in elderly (Thiazides) Dyslipidemia response curve

CCF (Spironolactones improve Minimal adverse effects

survival)
Monitor K levels with
spironolactone

B Blockers Coronary artery disease Asthma Can be used as monotherapy

HF Heart Block
Migraine
Tachyarrhythmia

A Blockers Prostatic Hypertrophy Heart failure Postural and 1st dose hypotension
(No DL and glucose intolerance)

CaCB Systolic HTN in elderly Heart Block Don’t use short acting DHPs
Angina Lead to acute infarction and death
Raynaud’s Phenomenon Prefer long acting
Pregnancy
SVT

ACEI Diabetic or other nephropathy B/L Renal artery stenosis Used for all grades of HTN
HF Hyperkalemia
CKD Pregnancy Don’t combine with ARBs
Previous MI

AT1 Antagonists ACEI associated cough B/L Renal artery stenosis

Diabetic or other nephropathy Hyperkalemia
HF Pregnancy

In Pregnancy Methyldopa B Blockers (Atenolol causes IUGR) Better avoid diuretics

Labetalol ACEI / ARB
Hydrazine HTN emergency =
Sodium Nitroprusside SBP > 180
CaCB (Nifedipine) DBP > 120
IV Labetalol, GTN, Hydrazine,
Sodium nitroprusside
 Anti-Anginal Drugs

Explain the pharmacological basis of the use of GTN to relieve acute anginal pain (20 marks)

PLAN
- Basis of angina
- GTN forms NO
- Explain the action on
● Distal veins
● Arterioles
● Coronary arteries

Angina is the ischemic pain of the heart, arising due to the imbalance between myocardial O2 supply
and demand (2)

GTN is a short acting organic nitrate that acts by relaxing smooth muscles. (1)

GTN is metabolized to release NO (1)

● Forms guanylyl cyclase
● Causes dephosphorylation of myosin light chains
● Increases cGMP that relaxes smooth muscles resulting in veno and vasodilation. (2)

They act on veins, arterioles and large coronary arteries. (1)

Vasodilatation in distal veins

● Reduces venous return due to venous pooling
● Reduces preload and ventricular end diastolic volume
● This decreases the myocardial O2 demand. (4)

Dilation of arterioles
 ● Reduces the peripheral resistance
● Afterload decreases
● Reduces the ventricular workload that results in reduced O2 demand. (4)

Dilatation of large coronary arteries

● Increases the redistribution of blood to the ischaemic regions
● Increases myocardial perfusion and the O2 supply. (4)

In addition, nitrates also reduce platelet aggregation

Therefore, GTN decreases the O2 demand of the myocardium and increases the O2 supply. This reduces
the mismatch between O2 demand and supply resulting in anginal pain relief.(1)

Describe the pharmacokinetic properties of the drug mentioned in 2.1 that would help in deciding the
route of administration. (10 marks )

Nitrates absorbed from the gut are subjected to extensive first pass metabolism in the liver and little
amount of drugs enter into systemic circulation. Since it is well absorbed from mucosal surfaces of the
mouth, the sublingual route is effective.

List 5 advices you would give to a patient regarding use and storage of GTN tablets (10 marks)

Advices on Usage
1) (Indications) Used immediately on onset or anticipation of chest pain or before any planned
exercise/ exertion.

2) Explain mechanism of drug

3) (Administration) Take sublingually (Crush one tablet with teeth and keep under the tongue. Do
not swallow the tablet)
 4) Take the tablet in a seated position, not while standing.

5) Can repeat the dose if pain persists after 5 min. If the pain persists after the 3rd dose, seek
medical advice immediately. (call an ambulance)

6) Inform about common side effects like headache, faintishness, flushing, tachycardia.

7) Take paracetamol in case of headaches and it will subside after a few days, but do not stop
taking the drug. If the headache is severe, spit out or swallow the tablet.

8) Avoid concomitant use of phosphodiesterase inhibitors Viagra (sildenafil) and alcohol.

9) If SE persists, seek medical advice.

Advice on Storage
1) Store in a cool, dark place (refrigerator)
In a dark/ brown glass bottle to avoid exposure to sunlight as they are unstable.

2) Discard tablets after 8 weeks. / Or after exposure to heat or air

3) Do not put cotton wool or cloths inside the bottle

4) Aluminum covered lid

5) Do not put into a plastic bottle even when traveling

A 55 year old man is diagnosed with stable angina and is given metoprolol. List four (4) other drugs
that are indicated in the management of this patient and give reasons for the use of each. (40 marks)

PLAN
CCB
● Act on Vascular SM
● Act on Cardiac SM
 ● Act on SA and AV node
- Indications Of DHP vs NDHP
Nitrates
- Mechanism of action
● Act on veins
● Act on coronary artery
● Act on arterioles
Antiplatelets
● Aspirin mechanism and benefit
● Clopidogrel mechanism and benefit
Statins
- Change in cholesterol levels
● 5 actions
Reduce atherogenesis
Antiinflammant
Stabilize plaque
Antioxidant
Reduces risk of rupture

1) Calcium Channel Blockers

DHP- Amlodipine/ Nifedipine/ Felodipine or non DHP- Verapamil/ Diltiazem (2 for any one)

- Symptomatic relief (1) by reducing oxygen demand and increasing oxygen supply (1)
- Block Ca2+ channels (1) to reduce intracellular ca2+ levels (1)

This causes :
a) Vascular SM relaxation (peripheral arterial dilation and reduced afterload)
b) Cardiac SM relaxation (reduced myocardial contractility)
c) Inhibition of SA and AV node and reduced heart rate (2 for any 2)

All the above 3 reduce myocardial oxygen demand and prevent angina (1)
● DHP mainly act on arteries while non DHP act on both arteries and heart (1)
● NDHP shouldn’t be compared with BB.
If a patient is given BBs DHP CCB should be used.
● When used as monotherapy NDHP are preferred
● NDHPs are C/I in the presence of heart failure
 2) Nitrates- ISMN / ISDN (2 for any one)
(Read the essay on GTN for a better answer)
Release NO (1)
Which activates guanylyl cyclase
Increasing cGMP (1)
This causes smooth muscle relaxation (1)
Leading to veno and vasodilation (1)
● Venodilation causes:
- Reduced venous return
- Reduced preload (1 for any one)
Reduce ventricular workload and myocardial O2 demand preventing angina (1)
● Coronary Artery Dilation causes (1)
- Redistribution of blood to ischaemic regions preventing angina (1)
● Arteriolar Dilation causes (1)
- Reduced afterload and ventricular load (1)
- Leading to reduced myocardial O2 demand preventing angina
- Reduces platelet aggregation

3) Antiplatelets (2 for any one)

Have a prognostic benefit (1)

a) Aspirin
Low dose Aspirin is the first line antiplatelet drug
At low doses (1) irreversibly phosphorylates and selectively inhibits COX1 but not COX 2 (1)
COX1 - Thromboxane formed. Platelet aggregation (1)
COX2 - Prostacyclin. Inhibits platelet aggregation (1)
Net effect is inhibition of platelet aggregation by aspirin (2)
Thereby prevent mainly arterial thrombus formation (1)

b) Clopidogrel
If hypersensitive to Aspirin or aspirin intolerance (1)
 Inhibit P2Y12 receptor of platelets (2)
Inhibit ADP dependent platelet aggregation (2)
Clopidogrel causes irreversible inhibition (1)
Thereby prevent mainly arterial thrombus formation (1)

4) Statins (Atorvastatin/ Simvastatin)

Reduce LDL and total cholesterol (1)
Increase HDL cholesterol (1)
- Thereby reduces atherogenesis (2)
- Stabilize atherosclerotic plaque
- Reduces endothelial inflammation (1 for any two)
- Has an antioxidant effect
- Thereby reduce risk of plaque rupture and ACS (2)
Given irrespective of LDL level
High intensity statins (Rosuvastatin > Atorvastatin) are used

● Ivabradine
● Nicorandil
● Ranolazine
Select any 4

Role of atenolol in the relief of anginal pain in a patient with ischaemic heart disease (25 marks )

PLAN
- Basis for pain
- (-) Inotropic
- (-) Chronotropic
- Blockade of JG cells
- Rebound Phenomenon
Angina is pain due to ischaemia of cardiac muscle as a result of lack of blood flow due to atherosclerosis
or rarely coronary spasm. Imbalance between myocardial oxygen supply and demand.

Atenolol is a cardioselective beta blocker

(-) Inotropic
- Reduced Force
- Reduces oxygen consumption
(-) Chronotropic
- Action on SA Node
- Reduces heart rate
- Increased time for diastolic filling
- Allows more myocardial perfusion (prognostic)

(Also reduce atrio-ventricular conduction with an elevated PR interval by blocking AV node)

This prevents ischaemia to the heart, relieving angina.

And preventing recurrence
(This improve exercise tolerance,reduce frequency and severity of angina episodes as well)

β blockade of JG cells decrease renin secretion and activation of RAAS system

Causing an increase in the ANP secretion leading to reduced Na and water retention. Thus it reduces the
blood pressure further reducing the workload and O2 demand of the heart.

Beta Blockers are the drugs of choice in patients with previous myocardial infarction because of their
proven benefit in secondary prevention

With prolonged administration

Due to reduced stimulation
β adrenergic receptors undergo up regulation
Undergo an increase in the receptor density.

As a result, with sudden withdrawal of drugs

 - Large proportion of receptors are exposed to catecholamine.
- Results in an increased heart rate and contractility
- Increasing the myocardial oxygen demand
- Worsens angina and may even lead to myocardial infarction or death.

This is known as “Rebound phenomenon “

And β blockers also may give some prognostic benefit as it can prevent ACS and mortality

(Metoprolol has a special advantage as it is a beta selective blocker therefore has less side effects caused
by the use of beta blocker such as exacerbations of asthma, hypoglycemia and high VLDL and low HDL
levels causing increased risk of CAD)

(Although the most commonly used beta selective blocker is atenolol, metoprolol can also be used
especially if a patient has renal impairment as it is metabolized by the liver)

● List five (5) contraindications of atenolol. (15)

Second or third degree heart failure.
People with progressing heart failure
Severe asthma
Patients on non-dihydropyridine CCBs
Hypersensitivity to beta blockers

● When are ACEI Preferred in Angina ?

Coexisting HTN, HF, Diabetes, CKD

● Is ISMN or ISDN preferred ?

 ISMN is preferred to ISDN
- more predictable response
- less frequent administration

● Symptomatic Relief
- BB
- CCB
- Nitrates
- Ivabradine
- Nicorandil
- Ranolazine
● Improvement of prognosis (secondary prevention)
- Antiplatelets
- Statins
- BB

Comparing Beta Blockers (Mainly MCQ)

Feature of the drug Examples Notable Benefits

Intrinsic Sympathetic Pindolol, oxprenolol, acebutolol, - Lesser bradycardia

Activity esmolol - Less rebound effect
- Less severe in angina
Mnemonic - P. AOE

'β1 selective’ - Metoprolol, Acebutolol Atenolol, - Recommendable in asthma

“Cardioselective“ Nebivolol, Bisoprolol, Esmolol (others worsen it)

Mnemonic - BAA MEN - And diabetes

(others mask hypoglycemic effect
and inhibit counter regulatory
symptoms)

Non-selective β-blockade Carvedilol and Labetalol - Cause arteriolar vasodilation and

and α1 blockade lower TPR

Membrane stabilizing effect Oxprenolol, propranolol, acebutolol, - Anesthetic blockade of local Na

esmolol channels
Water Soluble Atenolol, Nadolol, Sotalol - Predictable plasma conc
- Excreted by kidneys
Mnemonic - SAtaN - Dosage reduced in renal impairment
- Less likely to enter brain
- Less likely to cause nightmares

Lipid Soluble Propranolol, Metoprolol, Oxprenolol - Extensive liver metabolism

and Labetalol - High Vd
- Easily penetrates BBB
- Causes sleep disturbance, nightmares

List the functions of B Blockers

1) (-) inotropic and chronotropic effect on the heart
2) Reduced BP - Reduced CO > Reduced renin > Increased ANP
3) Opposes B2 mediated vasodilation
4) Reduces hepatic blood flow (Propranolol reduces its own metabolism)
5) Increase airway resistance
6) Precipitate bronchospasm
7) Reduce intraocular pressure and glaucoma
8) Inhibits glycogenolysis
9) Increased VLDL and reduced cholesterol
10) Reduces size and mortality in MI
11) Prevent recurrent ischemia and life threatening arrhythmia
12) Start a beta-blocker as soon as possible after an MI, when the patient is hemodynamically stable
and without contraindications
13) Effective in both supraventricular and ventricular arrhythmias
14) Metoprolol, bisoprolol, and carvedilol – Reduce mortality in HF
15) Reduces unpleasant symptoms of sympathetic overactivity in hyperthyroidism

Other points
Start low and go slow
Rebound phenomenon
Hypertension with non-selective α and β agonist
Don’t combine with verapamil
Beta-blockers, especially when combined with a thiazide diuretic, should be avoided for routine
treatment of uncomplicated hypertension in patients with diabetes
B Blockers are SAFE in pregnancy and NON TERATOGENIC but may cause IUGR (except labetalol)
Not contra-indicated in diabetes:
C/I - 2nd 3rd degree heart block and worsening HF

Acute Coronary Syndromes

A 60 years old previously healthy man was admitted to a teaching hospital with acute retrosternal
chest pain of 30 minutes duration.ECG shows ST elevations in leads 1,aVL,V4-V6and
was diagnosed to have an acute ST elevation myocardial infarction.

Enumerate the drugs prescribed for this patient during the first 30 minutes of admission. (40 marks)

PLAN
- Elaborate on the situation
- Basics in any emergency - ABC, cannula, O2
- Basics in an ACS emergency - Dual antiplatelets + Morphine + GTN
- Restoring perfusion (PCI or Thrombolysis)
- Antithrombin co-therapy

As the patient is having anterior STEMI, the goal is early perfusion therapy to restore coronary
perfusion to prevent. This can be done by percutaneous intervention and thrombolytic therapy and they
are indicated if present with 2 hrs and 12 hrs of onset of chest pain respectively.

First assess the ABC

Put him on cardiac monitoring
Obtain IV access
Give oxygen via face mask (or nasal cannula) if breathlessness is present.

1) Aspirin 150 - 300 mg chewed and swallowed, not enteric coated and clopidogrel 300 mg oral
 2) Sublingual GTN 0.3 – 1 mg (repeated as needed)
3) IV morphine 2.5 – 5 mg with antiemetic like metoclopramide

Which is then preceded by reperfusion therapy that aims to reopen the occluded artery as soon as
possible and establish coronary circulation.

Indications for reperfusion therapy. All must be present.

● Symptoms of >20 minutes
● Symptoms commenced within 12 hours
● ST elevation or presumed new left bundle branch block on ECG
● No contraindications to reperfusion therapy

Primary Percutaneous Intervention is the preferred method but should be performed within two hours
of an MI by an experienced team. Helps avoid some bleeding risks of fibrinolysis.

Fibrinolysis is done where primary PCI cannot be offered to STEMI patients within the recommended
timelines. Should be done within 12 hours. Door to needle time 30 min. The earlier the better
● Tenecteplase is given as a single IV bolus with the dose depending on the patient’s body weight.
Or Streptokinase (has a risk of allergies)

Thrombolytic therapy is followed by antithrombin co-therapy.

● Enoxaparin
Or Heparin
Given until revascularization has been completed
If not upto 48 hours
Helps reduce mortality
Monitor APTT while doing so

Indications of successful fibrinolysis

- ST-segment resolution >50% at 60–90 min
- Typical reperfusion arrhythmia
- Disappearance of chest pain
Apart from that ACEI, beta blockers (if the patient is hemodynamically stable only), statins can be given
which have mortality benefits.

EXTRA - Non reperfused patients

Refers to patients presenting 12 hours after the onset of pain or reperfusion therapy had not been
performed within 12 hours.

Aspirin, clopidogrel, high dose statins and an antithrombin agent (UFH, enoxaparin or fondaparinux)
should be given as soon as possible

EXTRA - STEMI Management during 24 - 48 hours

1) Reduction of myocardial energy consumption
- Atenolol or Metoprolol (Except in HF / Severe bradycardia)
- CaCB (If BB are contraindicated)
2) Prevent ventricular remodeling
- ACEI or ARB
3) Coronary vasodilation
- GTN sublingual or IV
4) Glycemic control
- Even if or no previous history of diabetes
- 5 to 11 mmol/l
5) Watch out for complications of an MI
- Acute LVF
- Cardiogenic Shock
- Mural thrombi
- Arrhythmias
- Pericarditis

EXTRA - Long term ACS Management

1) DAPT for 18 months
- Aspirin lifelong
- Clopidogrel (used alone if aspirin C/I)
- Gastric protection due to GI side effects
2) B Blockers to prevent reinfarction
- Commence within 24h
 - If stale and not contraindicated
3) Lipid lowering therapy
- High dose statins irrespective of cholesterol levels
- Omega 3 Fatty acids
4) ACE / ARB to prevent ventricular remodeling
5) Nitrates
- Long acting to prevent symptoms
- Short acting for acute symptomatic relief
6) Lifestyle changes
7) Risk factor control
- Blood glucose (HbA1c < 6.5)
- Blood pressure < 120/80
- LDL cholesterol < 1.8 mmol/l

EXTRA - Management of an NSTEMI / Unstable Angina

High risk patients for progression to myocardial infarction or death require urgent coronary angiography
and interventions.

Low risk patients can be managed with oral aspirin, clopidogrel, beta-blockers and nitrates.
An exercise stress test could be done. If positive, carry out early invasive management.
(+ test is an ST depression of 1 mm after exercise)

Thrombolytic therapy is not done for NSTEMI

Immediate management in an NSTEMI
1) Antiplatelet agents
2) Analgesia (GTN or morphine + antiemetic)
3) Plaque stabilization - Statins
4) Oxygen by nasal cannula
5) Antithrombins
- LMWH
- Heparin
- Fondaparinux
6) Glycoprotein IIB/IIIA inhibitors
- Abciximab
 - Tirofiban

A patient in the world has suffered a myocardial infarction 2 days ago His current prescription includes
aspirin, clopidogrel, atorvastatin, enalapril,atenolol,glyceryl trinitrate, isosorbide mononitrate,
nicorandil and enoxaparin

List 5 drugs from the above prescription that offer a survival benefit to the patient marks)
1. Aspirin
2. Clopidogrel
3. Atorvastatin
4. Enalapril
5. Atenolol
Enoxaparin also has survival benefit

(another qn) Five days later he was discharged with the following prescription.
● Aspirin 75mg nocte
● Clopidogrel 75 mg nocte
● Atorvastatin 40 mg nocte
● Ramipril 5mg daily

Comment on the appropriateness and the objectives of giving each of the medicines in the above
prescription.State if any other drug/s should be included and why. (30 marks)

Aspirin inhibits the cyclo-oxygenase pathway irreversibly and thus thromboxane (a prostaglandin
produced by platelets which promotes platelet aggregation) is inhibited. It is given as a lifelong
treatment (2) to improve the prognosis and reduce further thrombus formation. (1)

Clopidogrel inhibits P2Y12 receptor of platelets which inhibits ADP dependent platelet aggregation. (2)
Both of these are given as dual antiplatelet therapy for 12 months (2) to provide a prognostic benefit
(reduce reinfarction) and reduce recurrent cardiovascular events and further platelet aggregation at the
site of occlusion. (3)
Atorvastatin are statins which are lipid lowering drugs that competitively inhibit HMG CoA reductase
which is the rate limiting step of cholesterol synthesis. Statins decrease platelet aggregation, decrease
LDL cholesterol levels, increase HDL and have an anti-inflammatory action on the endothelium. It also
stabilizes atheromatous plaques and has antithrombin and fibrinolytic actions (3). Therefore, this
reduces the risk of reinfarction. (2)

Ramipril is an ACE inhibitor that prevents the conversion of angiotensin I to angiotensin II by inhibiting
angiotensin converting enzymes. It prevents ventricular remodeling, sodium and water retention and
vasoconstriction (3). Thus, it reduces myocardial oxygen demand and gives a prognostic benefit. (1) It
reduces the loss of functional myocardium and reduce the risk of immediate Heart failure as short term
benefit (2)

Prevent cardiac remodeling thus reduce the risk of HF, prevent vascular remodeling thus reduce the risk
of HTN as long term benefits. (3)

Metoprolol 50 mg daily (any cardio-selective beta blocker/ CCB)- to reduce myocardial oxygen demand
and also to improve the prognosis/ reduce mortality. (3)
GTN 300 µg SOS - a short acting nitrate for acute symptom relief. (no effect on mortality) (3)
(Pantoprazole – a proton pump inhibitor for gastric protection for any risk of GI side effects) (1)

How would you advise a previously healthy patient who had been discharged following treatment for
an acute anterior ST elevation myocardial infarction.

Aspirin (Life long)

“Aspirin may cause a little bit of burning sensation and reflux. If they become intolerable to come
back to the hospital”. Then try aspirin with a Proton Pump Inhibitor. If I can't tolerate it at all ,
stop the medication.

Clopidogrel (for 1 year)

”Generally a quiet drug”

Satin (Life long) Used not only for lowering of LDL, but also for stabilization of the plaque and
anti-inflammatory action on endothelium. Use high intensity statins (Atorvastatin, Rosuvastatin)
 Side effects are detected in the routine clinic visits. Statin causes transient rise in transaminases.
But the patients will not usually have symptoms. If the levels go beyond 5 times the upper limit
of normal, discontinue the drug temporally and restart and see.

But sometimes patients may complain of muscle pain (Myositis leading to rhabdomyolysis with
renal failure).

β- Blockers (Life long)

Side effects include wheezing, vivid dreams and impotence

ACE inhibitors (Life long)

Warn the patients about coughing

Short acting nitrates

Furosemide
If additional complaints are there

Lifestyle habits include dieting for weight loss and exercise.

List 5 contraindications of atenolol (15 marks)
1. History of asthma and bronchospasm
2. Uncontrolled heart failure
3. Prinzmetal angina
4.2nd or 3rd degree Av block
5. Marked bradycardia

A patient with chronic heart failure is diagnosed with persistent atrial fibrillation.
Name 2 drugs appropriate for achieving rate control in this patient (10 marks)
CCB verapamil (class 4 antiarrhythmic)
Beta blockers( class 2)
If rate control is inadequate during normal activities, digoxin can be added
(Rhythm control to restore sinus rhythm is achieved by amiodarone like anti antiarrhythmic drugs or
electric cardioversion)

Name a drug appropriate for long term anticoagulation and briefly describe its mechanism of action
(20 marks)

Warfarin ( long-term anticoagulation need to reduce the risk of stroke. To prevent that
thromboprophylaxis consider in IHD, HF, TIA, elderly, DM, valve diseases, HTN, thyrotoxicosis like
conditions )
Inhibits epoxide reductase which covert inactive vitamin K to active form (regeneration). Vitamin K needs
for carboxylation of vitamin K dependent clotting factors, two, seven, nine, ten. This prevents clot
formation.

Anticoagulants, Thrombolytics and Antiplatelets

Give reasons why tenecteplase is preferred over streptokinase for thrombolysis (30 marks)

1) No hypersensitivity reactions in Tenecteplase

Streptokinase is a protein produced by beta hemolytic streptococci
Antigenic properties of the drugs can cause hypersensitivity reactions.
High antistreptococcal antibody titer

Tenecteplase is produced by recombinant DNA technology

So it doesn't have any antigenic properties.

Furthermore streptokinase cannot be given within 4 days of a previous dose due to antibody
formation but tenecteplase can be given with no such restriction.

2) Bleeding risk is less as it is clot selective

Which is active more on fibrin bound plasminogen than plasma plasminogen
Unlike streptokinase which is not clot selective
And acts on both fibrin in clots and circulation and can lead to massive bleeding

3) More convenient to administer

Tenecteplase has a longer half life
And can be given as a single IV bolus
Streptokinase has a lower half life and is given as an IV infusion
 4) Thrombolytic property is high

Tenecteplase has the highest affinity to fibrins and greatest enzyme efficacy.
Thrombus resolution and patency of the vessel is high

5) Hypotension risk is less

List five absolute contraindications for thrombolytic therapy

1. Previous intracranial hemorrhage
2. Stroke of unknown origin at any time
3. Ischemic stroke with in 3 months
4. Malignant intracranial tumor
5. Intracranial structural cerebral vascular lesion
6. Suspected aortic dissection
7. Active bleeding or bleeding diathesis (except menstruation)
8. Significant head or facial trauma with 3 months
9. Gastrointestinal bleeding within one month
10. Non compressible punctures within 24 h

List five relative contraindications for thrombolytic therapy

1. Severe uncontrolled hypertension
2. Non-hemorrhagic stroke
3. Major surgery
4. Traumatic or Prolonged CPR
5. Active peptic ulcer
6. Pregnancy
 7. Noncompressible vascular punctures or recent invasive procedure

For streptokinase
- Prior exposure (more than five days ago) or prior allergic reaction to these agents
- Recent internal bleeding (2 to 4 weeks)
- Current use of anticoagulant

EXTRA - Indications in Thrombolytic Therapy

● Acute MI (Done within 12 h only. Door to needle time 30 min)
● Acute ischaemic stroke
- The ischaemic penumbra is a severely hypoperfused, non-functional, but still viable
cortex
- Surrounds the irreversibly damaged ischaemic core
- Elapsing time, more penumbra gets recruited into the core
- Tissue reperfusion is able to stop this degeneration
- Saving the penumbra should improve clinical outcome
- Main target of acute stroke therapy
- IV Alteplase given within 4.5 hours of a stroke
- Door to needle time 60 min
- Aspirin/Heparin should not be given before or within first 24 hrs of thrombolysis
● Massive PE with haemodynamic instability
● Limb threatening venous thrombosis
● Acute peripheral arterial occlusion

Monitoring done in thrombolysis

- constant neurologic and cardiovascular evaluation
- stopped urgently with any signs of neurologic deterioration
- stopped immediately with any bleeding complications
- If on concomitant heparin, protamine sulfate can reverse the heparin effect.

EXTRA - Antifibrinolytics
Tranexamic acid
Inhibiting binding of plasminogen and tPA to fibrin
Blocks conversion of plasminogen to plasmin
Inhibits fibrinolysis
Indications
- Hyperplasminaemic bleeding states
- After prostatic surgery, tonsillectomy, menorrhagia
- Reduce bleeding after ocular trauma
- Bleeding disorders such as von Willebrand disease and hemophilia

UFH vs LMWH (Credit - Praveen)

Criteria UFH LMWH

Synthesis Also naturally produced in mast cells Synthetic preparations only
Actions ● Increase rate of Antithrombin ● Action on antithrombin III 🡪 mainly
III-thrombin complex formation Inhibit factor Xa
🡪 inhibit thrombin ● Thrombin inactivation to a lesser
● Inhibit factor Xa and others extent
● APTT is prolonged ● APTT is minimally prolonged at
● Inhibits platelet function therapeutic levels
● Low to moderate platelet function
inhibition

Pharmacokine Absorption ● Not absorbed orally ● Not absorbed orally

tics ● Given IV or SC ● Given SC or IV
● SC – has erratic bioavailability ● SC - high bioavailability compared
● IM – not given due to to UFH
hematoma formation ● IM – not given due to hematoma
formation

Distribution ● Highly protein bound ● Less protein bound

● Highly negatively charged – ● Pharmacokinetics are more
binds to a large array of blood predictable – fixed weight dosing
components – poorly can be given
predictable pharmacokinetics ● Does not cross placenta
● Does not cross placenta

Metabolism
 Clearance ● By endothelial cells and ● Principally cleared renally – avoid
macrophages – not affected by in patients with Cr
renal or hepatic impairment at Clearance<30mL/min
therapeutic conditions (dose
reduction should be done ● Longer half-life – once or twice
according to SLSF) daily dosing

● Rapid onset of action with short

half-life (action dissipates 4-6
hours after stopping infusion)

Adverse effects ● Hemorrhage ● Hemorrhage

● Heparin induced ● Hematoma at injection site
thrombocytopenia (HIT) ● Lower incidence of HIT - but
● HIT type 1 – benign, dilutional should still be avoided in patients
● HIT type 2 – Ab formation with Hx of HIT type 2 (if Ab are still
against heparin-platelet factor 4 present)
complex 🡪 thrombocytopenia ● Maternal osteoporosis when used
and thrombosis (stop heparin) long term in pregnancy
● Maternal osteoporosis when
used long term in pregnancy

Differences in Clinical ● Erratic SC bioavailability (IV ● High bioavailability in SC

Applications preferred)

● Weight based dosing ● Fixed doses can be given

● Unpredictable pharmacokinetics ● More predictable

– APTT monitoring is needed pharmacokinetics – monitoring not
needed (except in renal
impairment)

● Rapid onset of reaction with ● Long half-life – once or twice daily

short half-life dosing is possible

● Not used in outpatient ● Can be used in outpatient

treatment treatment

● Can be used in severe renal ● Avoided or Dosage adjustment in

impairment renal impairment

● Quickly reversible with ● Not quickly reversible

protamine sulfate
● Suitable for treatment of MI
after major surgery. (due rapid
short action and reversibility)
 ● Inhibition of platelet function ● Low to moderate inhibition of
platelet function

● Higher incidence of HIT ● Lower incidence of HIT

List 3 advantages of enoxaparin over unfractionated heparin.

1. No need of administration via parenteral route
2. APTT monitoring is not required
3. As half life is more once daily dosing can be given
4. Bleeding risk is less
5. Heparin induced thrombocytopenia risk is less
6. Osteoporosis in long-term exposure ( mostly in pregnancy) is less

Briefly explain why enoxaparin is given with Tenecteplase. (20 marks)

Tenecteplase is a rtPA (2) that converts plasminogen to plasmin, so that plasmin can degrade fibrin to
fibrinogen degradation products (2) which dissolves the thrombi in occluded vessels. It is given as
primary reperfusion therapy that results in the opening of occluded vessels to reestablish coronary
circulation. (2)

Even though the persistent clot gets degraded by Tenecteplase, the defect of ruptured plaque is still
there it means it will be susceptible for future clot formation (2)

Enoxaparin is a low molecular weight heparin (2) that inhibits coagulation by binding and potentiating
the action of antithrombin III by deactivating the factors Xa and IIa (very little action on factor II). (3)
deactivating the indirect clotting pathway

An IV bolus of Enoxaparin is given as antithrombin co-therapy following tenecteplase. Enoxaparin can

also reduce the damage from mural thrombi following AMI, thus further preventing the chance to
reduce the risk of reinfarction (2) and reduce mortality (3) (reduce 30-day mortality).
risk of venous thromboembolism, and the formation of embolism of reinfarction. (2)
A 45-year-old man is admitted with a history suggestive of ischaemic chest pain of 1 hour’s duration.
He has no significant past history.He was given 300mg of aspirin to be chewed and swallowed, 300mg
of clopidogrel and 40mg of atorvastatin orally. Oxygen 2L/min was administered via nasal cannula and
0.5mg of GTN was administered sublingually.

Applying your knowledge on the pathophysiology of acute myocardial infarction, explain why he was
given aspirin and clopidogrel (30 marks)

In myocardial infarction is the irreversible death of cardiac myocytes secondary to reduced O2 supply.

This patient has suffered an ischemic chest pain, which could be a result of coronary artery getting
blocked by a thrombus, resulting in reduction of coronary blood flow. the thrombus could be likely arisen
due to disruption of atherosclerotic plaque. (3)

Whenever a patient is admitted following any event of acute coronary syndrome, immediate therapy
includes dual antiplatelet therapy (1)

DAPT is the combination of

● Aspirin 150-300 mg chewed and swallowed
● Clopidogrel 300 mg oral
Both are antiplatelets. (2)

Aspirin at low doses causes an irreversible inhibition of cyclooxygenase pathway (COX-1) (3)
Results in inhibition of thromboxane A2 and prostaglandin (2).
Thromboxane A2 produced via the COX-1 pathway causes platelet aggregation (2)
and vasoconstriction (2).
Therefore, low dose aspirin prevents further thrombus formation.

Also, Aspirin is not enteric coated to allow faster absorption after dissolution (chewed and swallowed)
(1)

Clopidogrel irreversibly inhibits the P2Y12 receptors on platelets (3).

Inhibits ADP dependent platelet aggregation (2).
Is a prodrug which is converted into the active form in the liver.

In MI pain starts even before the platelet plug forms. therefore, during immediate management
Dual antiplatelet therapy is given to prevent further thrombosis (2)
● By reducing platelet aggregation (2)
● Prevents reinfarction and death of myocytes
● Thus reducing mortality. (2)

Here loading doses are given for quick action and As they inhibit platelet action in two different
mechanisms it is more potent than giving alone (1)

Name a drug appropriate for long term anticoagulation and briefly describe its mechanism of action.
(20)

Warfarin is a competitive vitamin K antagonist.

It is given orally and has a long half life and is metabolized in the liver and some excreted in urine.

Vitamin K is an essential component for the Gamma carboxylation of clotting factors namely – II, VII, IX,
X.

Gamma carboxylation is essential for those factors to get activated binding to Calcium ions.

Once warfarin inhibits Vitamin K, those coagulation factor activation is impaired and risk of thrombosis
is reduced and the whole clotting pathway is affected. (stroke prevention in AF)

Treatment should be commenced in small doses

As there is increased risk of bleeding with warfarin INR should be monitored to keep it <4.

There are some adverse effects of warfarin long term therapy such as increased risk of bleeding, skin
necrosis.

Pharmacokinetics of Warfarin
- 100 percent bioavailable
 - Crosses the placenta
- Low Vd
As Warfarin is metabolized by the liver it is impacted by enzyme inhibitors and inducers
A synergistic anticoagulant action in liver disease

Diuretics

Name Action Indication Side Effects Other Important Points

Loop Diuretics Inhibits Na/K/2CL transporter Acute Pulmonary Severe NSAIDS or Probenecid competes
(Furosemide, (A.Loop of Henle) Edema dehydration with loop diuretics for secretion in
Ethacrynic Acid, the PCT
Bumetanide, Increase in Mg2+ and Ca2+ Mild Hyperkalemia Hyponatremia
Torsemide) excretion (less than As they exert their diuretic effect
ARF thiazides) on the luminal side of the tubule,
Induce expression of COX-2, this impairs their action
PGE2 - Increases renal blood HTN + Renal Dose related
flow impairment hearing loss
(reversible) Most loop diuretics are
Hypercalcemia sulfonamides (ide)
(medical Hypokalemic C/I
emergency) metabolic - Hepatic encephalopathy
alkalosis - Dehydration
- Hypo Na
Hyperuricemia - Hypo K
Hypercalciuria
Mg depletion

Thiazides Blocking the Na+/Cl− HTN Increased urine Less powerful and better
(Bendroflumeth transporter (DCT) frequency tolerated than loop diuretics
iazide, HF
Hydrochlorothi Loss of Na and Water Hypokalemic Given orally (Chlorothiazide only
azide) Increased Ca reabsorption Hypercalciuria Metabolic IV)
(nephrolithiasis) Alkalosis
Indapamide is a Thiazide like drug
 Nephrogenic DI Hyperglycemia
(Pancreas Thiazides are also sulfonamides
releases insulin)

Hyponatremia
Gout
Impotence
Glaucoma

Potassium Antagonize the effects of Hyperaldosteronism Hyperkalemia C/I

sparing aldosterone in - Chronic Renal
diuretics collecting tubules Liddle’s Syndrome (Hyperchloremic Insufficiency
Metabolic - Liver disease
(Amiloride, Loss of Na and water Acidosis-rare) - C3PYA inhibitors
Triamterene, K is not lost or reabsorbed (grapefruit, fluconazole,
Spironolactone, Action on other diltiazem)
Eplerenone) steroid receptors
(Gynecomastia,
Impotence)

ARF
Kidney Stones

Carbonic CA enzyme is mostly found in Glaucoma Acidosis Diuresis within 30 minutes,

Anhydrase PCT maximal at 2 hours, and persists
Inhibitors Urinary Potassium for 12 hours after a
alkalinisation Wasting single dose

Metabolic alkalosis Phosphaturia and Tolerance develops after 2-3 days

hypercalciuria
Acute mountain C/I
sickness - Alkalization of urine
(reduces NH4 excretion
leading to
encephalopathy)

Osmotic Filtered from glomerulus but Reduce intracranial Mannitol is Mannitol is poorly absorbed so
Diuretics not reabsorbed, leading to pressure rapidly given IV. Not metabolized.
(Sucrose, water accumulation distributed in the
Mannitol) Prompt removal of ECF Used cautiously in patients with
toxins - Dehydration even mild renal insufficiency
- Hyperkalemia
Reduce intraocular - Hypernatremia
pressure before
ophthalmologic Hyponatremia if
 procedures retained

ARF

ADH Inhibit the effects of ADH in SIADH Nephrogenic DI V1 receptors - Vasculature, CNS
Antagonists the collecting tubule V2 receptor - Kidney
(Conivaptan HF RF
tolvaptan) Specific
Polycystic Kidney Dry mouth
disease

A patient with congestive cardiac failure is admitted to the ward with worsening shortness of breath.
On examination he is hemodynamically stable with a blood pressure of 120/80 mmHg and SaO2 of
96% on room air. He has pitting oedema of both legs and there are bilateral fine basal crepitations on
auscultation of the lungs.

Explanation - This patient is presenting with pulmonary oedema. (Bilateral fine crepitations). Since his
saturation is 96% it’s not urgent to give oxygen (But should continuously monitor with the saturation
probe).

No need of inotropes like dobutamine and no hypertensive emergency is detected. Reliving the
pulmonary oedema would relieve the symptoms. We have to consider acute heart failure management.

Name the drug you would administer immediately to relieve his symptoms stating its route of
administration. (10 marks)

Drug- Furosemide (5) Route- Intravenously/ IV (5)

Explain the pharmacological basis for using the drug you mentioned above (35 marks)

PLAN
 - Define CCF
- Principle - Diuretics are used for symptomatic relief
- Immediate vasodilator action of loop diuretics
- Delayed diuretic action
● Direct action on the Ascending Limb
● Indirect effect on Descending Limb
- Conclusion = Reduced Pulmonary congestion + LV filling pressure

Pathophysiology - (bit extra)

- Congestive heart failure
- Reduced ejection fraction
- Would give rise to stasis of blood within the ventricles
- Due to reduced emptying of atria, back pressure occurs.

In the left side - Pulmonary veins transmit this pressure to the lungs. Then it gives rise to pulmonary
oedema. Pulmonary oedema is the reason for bilateral crepitations.

On the right side - IVC and SVC pressure is increased. This gives rise to bilateral pitting oedema in the
legs. Due to increased venous pressure, increased filtration in the capillary level occurs.

This is the reason for increased fluid in interstitial space or oedema.

COP = SV x HR (Stroke volume and heart rate should be reduced).

In this patient LV dysfunction has caused pulmonary hypertension / congestion with bi basal fine lung
crepitation which is a sign of pulmonary oedema (2)

Hence for immediate symptomatic relief, reduce preload is needed (3)

IV furosemide is a potent loop diuretic (1)

It reduces the preload by two mechanisms
- Immediate direct vasodilatation
- Diuresis (4)
 1) Immediate action of vasodilatation is a result of release renin, AT2 and PGE (3)
- Faster than its diuretic effect
- Provide a sudden relief of pulmonary oedema
- By reuptake of fluids into the veins (4)

2) It inhibits the Na-K-2Cl transporter (1) on the thick ascending limb of loop of Henle (1)
- Ascending limb is normally impermeable to water
- Inhibits the reabsorption of these ions (1)
- Promotes their secretion to tubular lumen (1)
- Reduces renal medullary hypertonicity and disrupts the counter current mechanism (1)
- Inhibits water reabsorption in the thin descending limb of loop of Henle (2)
- Promoting water diuresis and increasing urine output (1)
- Reduces cardiac preload / offload heart (1)

IV furosemide also
- Reduces pulmonary congestion (1)
- Reduces venous return to the heart
- LV filling pressures in heart failure (1)
before a measurable increase in urinary output occurs (1)
Offloading the heart is the main mechanism of using loop diuretics.

Hence, IV furosemide gives immediate symptomatic relief in CCF (1)

Pharmacokinetics
Furosemide is rapidly absorbed. For increased bioavailability it is given intravenously in acute heart
failure. It is more potent compared to thiazide diuretics.

Potency is the dose needed to exert a certain effect.

Side Effects
● Due to polyuria, it can cause severe dehydration. It can also cause distress to this patient.
● Hypokalemic metabolic alkalosis could occur.
List three (3) drugs that improve survival in patients with congestive cardiac failure. (15 marks)
- ACE inhibitors - captopril, enalapril
- Potassium sparing diuretics-Spironolactone
- Beta blockers- Metoprolol, Carvedilol, Bisoprolol (only these 3 drugs are accepted).
- ARNI- sacubitril-neprilysin
- SGL-2 inhibitors- empagliflozin, canagliflozin
- ISDN-Hydralazine combination (only the combination, individual drugs won’t give a mortality
benefit).
- Ivabradine

A patient with chronic heart failure is diagnosed with persistent atrial fibrillation.
Name 2 drugs appropriate for achieving rate control in this patient. (10)
Calcium Channel blocker
β-blockers

Lipid Lowering Drugs

Describe the mechanism of action of atorvastatin. (20)

Atorvastatin is a statin drug which lowers the lipid levels in the body which is specially given for the
patients with increased cardiovascular risk.

Statins are structural analogs of HMG CoA Reductase

- Competitively inhibit HMG CoA reductase enzyme
- So that production of cholesterol is inhibited.

● Dose dependent reduction in plasma total cholesterol and LDL cholesterol.

- Induce high affinity LDL receptors in the liver
- So that the cholesterol in LDL will be taken by the liver
- Increasing fractional catabolic rate and extraction of LDL precursors
 - Reducing the blood cholesterol level.

Statins also cause small elevation of HDL and decrease in TG in plasma.

Other functions of statins

- Decrease vascular inflammation
- Oxidative stress
- Help to stabilize the atherosclerotic plaque
- Preventing embolism.
Slight regression of the plaque also can be seen with statin therapy.

Pharmacokinetics
- High first pass metabolism
- Metabolized in liver extensively
- Cholesterol synthesis occurs predominantly at night. Given by mouth in the evening

Along with the above benefits they also show some adverse effects.
Myositis, rhabdomyolysis, myopathies are seen in statin therapy especially when combined with other
lipid lowering drugs.

They are more prominent in patients with a history of muscle toxicity, alcohol intake, renal impairment
and hypothyroidism. Statins are also contraindicated in pregnancy.

Describe the precautions you would take when prescribing this drug.

First the indication for the drugs should be considered in primary and secondary prevention.

In primary prevention
● All adults with type 1 diabetes over 40 years, who are of 10 years of disease, who have
established nephropathy or other CSV risk factors.
● For type 2 diabetes if a 10 percent ten year risk of developing CVD
● All patients with CKD for primary and secondary prevention
In secondary prevention
 ● Used in patients with already established CVS diseases.

Then contraindications have to be excluded such as pregnancy, muscle diseases, active liver disease.
Teratogenic in pregnancy

Before starting the drugs some investigations have to be done.

- Liver profile – To see current lipid levels
- Hba1c – To exclude diabetes
- Renal functions test – To exclude renal disease
- AST/ALT levels – To exclude active liver disease.
- TSH – To exclude hypothyroidism. If hypothyroid, should be corrected before starting therapy.

If a patient has persistent generalized unexplained muscle pain, whether associated or not with previous
lipid-lowering therapy, measure CK levels
- If > 5 times upper limit remeasure after 7d
- If still the same don’t start
- If raised but less than 5 start at a lower dose

Avoid in active liver disease or persistent elevation of transaminases

Increased incidence of myopathy
- Fibrates
- Lipid lowering doses of nicotinic acids
- Fusidic acid
- (Macrolides, Imidazole, Triazoles)

Writing Discharge Prescriptions

Write an appropriate discharge prescription for the long term a patient discharged after a STEMI (25
marks)

22.12.2020
Mr XYZ
60 years
Aspirin tablet 75 mg PO nocte * 1 week
Clopidogrel tablet 75 mg PO nocte * 1 week
Atorvastatin tablet 40 mg PO nocte * 1 week
Enalapril tablet 5 mg PO mane * 1 week
Atenolol 50 mg PO BD * 1 week
Glyceryl trinitrate tablet 300 micrograms SL PRN – 10 tablets
(PPI for gastric protection and aldosterone therapy also can be added)
(signature)
Dr A
Colombo South Teaching Hospital
Colombo
SLMC registration number: 123456
Telephone: 077000000

Mr. Mendis recovered with your initial management and was treated with co-amoxiclav 625mg tds
and clarithromycin 500mg bd as he was found to have a mild community acquired pneumonia. He
was discharged from the hospital on day 3 with a plan to review him in the clinic in 1 week.
Write a prescription for this patient on discharge. (25 marks)

Date (1)
Name - Mr. K. Mendis(1)
Age – 30 years (1)
Rx
PREDNISOLONE (2) 50mg (1) PO (2) mane (1) 2 days ( until the 5- 7 day course is completed)
SALBUTAMOL (2) 200µg (1) MDI (1) SOS (2)
BUDESONIDE (2)300µg (1) DPI (1) b/d (1)(high dose inhaled corticosteroid)
CO-AMOXICLAV 625mg PO tds* (1) 1 wk
CLARYTHROMYCIN 500 mg PO bd* (1) 1 wk
Dr ..........(1)
 signature
SLMC Reg No.- (1)
Tel. No.- (1)

*These two drugs are mentioned because they are given in the question as this patient is having mild
the community acquired pneumonia. In a normal asthma discharge prescription, those two drugs
SHOULD
NOT BE INCLUDED.

He recovered with your initial management and was treated with co-amoxiclav 625mg tds and
clarithromycin 500mg bd as he was found to have a mild community acquired pneumonia.

He was discharged from the hospital on day 3 with a plan to review him in the clinic in 1 week.Write a
prescription for this patient on discharge. (30 marks)

Date:
Mr: S Perera
Age : 25 years
(5 marks)
Rx: PREDNISOLONE 50 mg PO mane --- 2 days ( until the 5- 7 day course is completed)
SALBUTAMOL 200 µg MDI SOS
BUDESONIDE 300 µg DPI bd
CO AMOXICLAV 625 mg PO tds 1 Week
CLARITHROMYCIN 500 mg bd 1 week
(4*5 = 20)
Dr. ……………
SLMC Reg No………..
T.P NO………..
(5 marks)
A previously healthy 60 year old Mr. S. Weerasekara was admitted to the emergency treatment unit
with typical ischemic type chest pain of 3 hours duration. He was diagnosed with acute anterior ST
elevation myocardial infarction (STEMI). A decision was taken to administer a thrombolytic drug.

The patient had an uneventful recovery and was discharged home, 5 days after admission
Write an appropriate discharge prescription for this patient. (25 marks)

Date (1)
Mr. S. Weerasekara, (1)
60 yrs. (1)
Rx
ASPIRIN tablet- 75 mg PO nocte x 1 week
CLOPIDOGREL tablet- 75 mg PO nocte x 1 week
ATORVASTATIN tablet- 40 mg PO nocte x 1 week
ENALAPRIL tablet- 5 mg PO mane x 1 week
ATENOLOL 50 mg PO bid x 1 week
GTN tablet 300mg SL SOS (sublingually, as needed)
(Pantoprazole for GI protection) (1 marks)
Dr ..........(1)
signature
SLMC Reg No.- (1)
Tel. No.- (1)

A 45 year old man is admitted to hospital with acute severe asthma. He has no life threatening
features. Write a discharge prescription for this patient (25 marks)
Date: ……….
Mr. ……………..
Age: 45 yrs.
RX Prednisolone 50 mg PO mane
Salbutamol 200µg MDI SOS
Budesonide 300µg DPI b/d
5 days
 Dr. ……………………
SLMC Reg. No. ………….
TP no. …………………

A 30 year old man who presents with recurrent attacks of wheezing is diagnosed as having bronchial
asthma. He prescribed dry powder inhalers of beclomethasone 400 micrograms twice daily and
salbutamol 200 micrograms to be taken as required. Write a prescription for this patient. (10 marks)
Date…………
Mr. ……………..
Age: 30 yrs.
RX Beclomethasone 400µg Dry Powder Inhaler
Salbutamol
200µg MDI
b/d
SOS
Dr. ……………………
SLMC Reg. No. ………….
TP no. …………………

RS MODULE

Mr S.Perera, a 25 year old man with chronic asthma, is admitted to the emergency treatment unit with
acute severe asthma. He had been on beclometasone dipropionate 200 micrograms metered dose
inhaler twice daily and salbutamol 100 micrograms metered dose inhaler as required.

Describe the drug treatment of this patient within the 1st 30 minutes of admission. (30 marks)
(Acute severe asthma is defined as)
- Unable to talk sentences in one breath
- Respiratory rate > 25
- Pulse > 110
- Arterial oxygen saturation >92%
- PEF 33-50%

Drug Management of Acute Severe Asthma

1) Humidified high flow Oxygen via face mask/nasal cannula (40-60 percent)
SpO2 value maintained at 93-95%

2) Inhaled B2 agonist : Salbutamol 5 ml via pMDI + spacer or nebulizer

Repeated every 10-20 minutes as needed

3) Short acting Muscarinic Antagonist Ipratropium Bromide 0.5 mg

together with salbutamol via oxygen driven nebuliser/ MDI with spacer every 4-6 hourly

4) Oral Prednisolone 40mg – 60 mg mg (5 marks)

or IV hydrocortisone 100 mg every 6 hours if vomiting/ oral intolerable (5 marks)

5) Can add IV MgSO4 and aminophylline

Other Points
● Assess the patient for dyspnea, respiratory rate, pulse rate, oxygen saturation.
● Exclude other causes for breathlessness (HF, Foreign body, pulmonary embolism)
● Arrange immediate transfer to ICU if the patient is drowsy, confused or silent.
● Check response of symptoms and saturation frequently. Measure lung function after 1 hour.
● If not improving the symptoms, discuss with seniors.

If the patient does not respond to steps 1 to 4 or life threatening features are present
Life threatening features
 - Silent chest / feeble respiration
- Cyanosis
- Exhaustion
- Hypotension
- Bradycardia / Arrhythmia
- PEF <33 percent

We can use IV MgSO4 or IV Aminophylline

Describe the pharmacological basis for the use of Salbutamol in the treatment of acute severe asthma
(25 marks)

PLAN
- Pathophysiology of asthma
- Mechanism (Adenylyl cyclase, CAMP)
- Functions
a) Bronchodilation
b) Inhibit bronchoconstrictor mediators
c) Inhibit microvascular leakage
d) Increased mucociliary transport
- Delivery and dose
- Side effects

Pathophysiology
Asthma is a chronic disease of airways characterized by airway hyper responsiveness,
bronchoconstriction, increased inflammation of the airways. Acute asthma is due to reduced compliance
with medication or exposure to allergens could also increase the bronchoconstriction.

Salbutamol is a B2 adrenergic agonist with relative (not absolute) B2 selectivity

Mechanism of action
● Salbutamol acts on beta 2 and activates
● Stimulates the adenylyl cyclase
● Formation of intracellular CAMP (Ca2+ enters cells causing relaxation)
 1) Beta-2 receptors on the airway cause bronchodilation.
2) Salbutamol also inhibits the release of Bronchoconstrictor mediators by stabilizing mast cells.
3) Inhibit microvascular leakage
4) Increased mucociliary transport are also mechanisms of actions that salbutamol relieves the
acute bronchoconstriction.

These mechanisms increase the entry of air into lungs providing relief
Pharmacokinetics
Delivered via inhalation to increase the deposition in the airway
Resulting in greatest local effects with minimal systemic toxicity
Aerosol deposition depends on particle size, pattern of breathing and the geometry of the airway.
Nebulization of salbutamol is done in acute severe asthma via nebulizer.
Dose used in acute severe asthma- 5 mg

Pharmacodynamics
Bronchodilation is maximal within 15 minutes and persists for 3–4 hours.
This gives rapid relief of symptoms in acute severe asthma
All can be diluted in saline for administration from a hand-held nebulizer.
If patient cannot be administered a MDI
Doses should be titrated according to a clinical response as needed

Side Effects
Hypokalaemia
Tachycardia in higher doses

A 30 year old man who presents with recurrent attacks of wheezing is diagnosed as having bronchial
asthma. He prescribed dry powder inhalers of beclomethasone 400 micrograms twice daily and
salbutamol 200 micrograms to be taken as required.

Described the pharmacological basis for the use of beclomethasone in the management of bronchial
asthma. (30 marks)
PLAN
- Pathology of asthma
- Functions of cytokines in asthma
- Importance of steroids
● Inflammatory cytokines
● Prevent Hyperreactivity
● Minimize Exacerbation
● Constrict Engorged vessels
● B potentiation
● Inhibit infiltration
- Dosage, Routes,S/E

Asthma is a chronic reversible obstructive airway disease. It is due to airway hyper responsiveness and
bronchial inflammation. Therefore it causes airway limitation. This is mediated by IgE immunoglobulins
which are attached to Mast cells during sensitization. On 2nd exposure to the allergen it causes Mast cell
degradation by attaching to IgE antibodies.

It causes the release of Histamine, Tryptase, Leukotrienes, Prostaglandins and other cytokines.
These cytokines :
1. Attract and activate eosinophils
2. Stimulate IgE production by B lymphocytes
3. Stimulate mucus production

Beclomethasone is a steroid and an anti-inflammatory agent

Reduces expression of genes needed to produce these cytokines
1. Inhibit production of inflammatory cytokines
2. Decrease bronchial hyperreactivity
3. Decrease exacerbation of asthma
4. Constrict engorged vessels
5. Potentiate effects of β receptor agonist
6. Inhibit infiltration of asthmatic airway by Lymphocytes, Eosinophils and Mast cells

This reduces the level of bronchial responsiveness by acting as a preventer. Enables better entry of the
reliever therapy into the airways.
The dose should be titrated to the lowest level at which effective control of asthma is maintained.
Routes of admission are by Inhalation (MDI), Oral and IV. Steroid can be delivered orally straight to the
respiratory tract with minimal systemic absorption.

Adverse effects include oropharyngeal candidiasis, hoarseness, osteoporosis and cataract and growth
retardation in Children

Patient should be advised to gargle and expectorate after each time of inhalation to prevent

A patient with acute severe asthma is treated with nebulized salbutamol, nebulized ipratropium and
intravenous hydrocortisone.

Describe the pharmacological basis for use of ipratropium in this patient (25 marks)

PLAN
- Pathophysiology
- Dose and frequency
- Short acting, rapid onset
- Functions
1) Prevent bronchoconstriction (M3)
2) Reduce bronchial secretions (M3)
3) Inhibits Ach from efferent nerve endings

Asthma is a chronic reversible obstructive airway disease. (2) It is due to airway hyper responsiveness (1)
and bronchial inflammation. (1) This is mediated by IgE. (1) Therefore, it causes airway limitation. It
causes dyspnea, wheezing (1)

Life threatening emergency (1)

- Nebulized with Ipratropium Bromide
- 0.5mg every 20-30 min
- And then 4-6 hourly if not improving (2)
Ipratropium is an antimuscarinic (2)
- Short acting (2)
- Onset of action within a few minutes.

M3 stimulation in bronchi
● Bronchoconstriction by contracting bronchial smooth muscle
● Increased bronchial secretions (2)

Ipratropium Bromide competitively (2) blocks the action of Ach at muscarinic receptors. (1)

Also inhibits Ach released from efferent endings of the vagus nerve in the airways. (2)

This leads to,

1. Reduced bronchial smooth muscle contraction leading to bronchodilation (2)
2. Reduce mucus secretion and edema of the airway (2) Therefore, it relieves asthma. (1)

Inhaled in high doses because of its poor absorption into the circulation
Longer acting ones include tiotropium, aclidinium and umeclidinium

A 25 year old man admitted to the ward with acute severe asthma is ready to be discharged from the
ward after 3 days of treatment. The plan is to see him at the clinic after 1 week.

Name the drug to be administered if the patient does not respond to the current treatment and state
its mode of administration. (10 marks)
IV MgSO4 (A tocolytic agent)

List 2 precautions you should take when administering the drug mentioned in 1.2 (10 marks)
- Adjust the dose of hypnotics if given together with MgSO4 as there can be an additive central
depressive effect.
- Not suitable for pregnant women as it is teratogenic.
 List three (3) precautions you should take when administering the drug mentioned in 1.2.2 (15 marks)
- Monitor electrolyte levels in the blood before administering and throughout
- Monitor BP, RR, and UOP before administering and throughout
- Monitor signs of overdose (nausea, slurred speech, drowsiness, double vision, patellar reflex)
- Adjust the dose of hypnotics if given together with magnesium sulfate due to occurrence of
attitude central depressive effect
- Check whether the patient is pregnant because magnesium sulfate should be avoided in
pregnancy

Compare and contrast the pharmacological properties of Salbutamol v Salmeterol v Formoterol and
explain how these differences relate to their clinical uses

Salbutamol Salmeterol Formoterol

Target substrate B2 selective agonist B2 selective agonist B2 selective agonist

Specificity Moderately High Very High High

Onset of action Fast - 15 min Slow Fast

Duration of action Short (3-4h) Long (>12h) Long (>12h)

Agonist activity Full Partial Full

Lipid Solubility Low High Moderate

In general, β-adrenoceptor agonists are best delivered by inhalation. This results in the greatest local
effect on airway smooth muscle with the least systemic toxicity. All three drugs can be used as inhalator
preparations and thus suitable for asthma treatment.

The aim of using beta agonist is to relieve the symptoms occurring due to bronchoconstriction. This can
occur in an acute setting or some patients may experience that in night episodes also.

Salbutamol is a SABA whereas Salmeterol and formoterol are LABA.

SABA, as they have a duration of action of 3–6 h, they have a rapid onset of bronchodilation and are,
therefore, used as needed for prompt symptom relief.
Salmeterol and formoterol can both be used as LABA.
In formoterol significant bronchodilation, which may persist for up to 12 h, occurs within minutes of
inhalation of a therapeutic dose. Its major advantage over many other β2-selective agonists is this
prolonged duration of action, which may be particularly advantageous in settings such as nocturnal
asthma.

Formoterol sustained action is due to its insertion into the lipid bilayer of the plasma membrane, from
which it gradually diffuses to provide prolonged stimulation of β2 receptors.

Although salmeterol is also lipophilic, the intermediate lipophilicity of formoterol means that a far higher
proportion of formoterol is retained in the extracellular space.

The result is a rapid diffusion of formoterol to B2receptors and a fast onset of effect. Salmeterol diffuses
more slowly through lipid regions and its onset of action is delayed.

Briefly describe the advice you would give him regarding the correct use of a MDI (30 marks)

Preparation
● If the spacer is present connect mouth part of the inhaler to the spacer
● Mouth must be empty.
● Keep the inhaler horizontally.
● Remove the cap.
● Shake the aero chamber (spacer) with the inhaler.

Inhalation
● Sit or stand, head slightly back
● Put the mouthpiece between your teeth and close your lips to form a good seal.
● Before pressing, exhale slowly and completely.
● Now press the inhaler canister 4 once and start inhalation. Slowly and deeply.
● Hold breath for 10s and exhale slowly
 ● Repeat until Rx dose.
● After inhaling corticosteroids, rinse your mouth with water, gargle and spit.

Cleaning
● If you use a spacer device, wash it at least once a week.
● Dispatch aero chamber.
● Wash all parts of inhaler, except the spacer (air dry it)
● Dip two halves in a bowl with warm water and mild detergent
● Do not rub the inner surface with a cloth or a brush.
It might promote deposition of the drug in the spacer
● Rinse with clean water
● Place it to air dry without exposing to heat or sunlight

Using a MDI alone is not recommended in children below 5 years and those who have poor hand-breath
coordination thus a spacer can be used.
When using in children below two years use MDI + spacer + face mask
Between 2-5 MDI + spacer
In adults there is no significant difference between a pMDI ± spacer and a DPI.

EXTRA - PREVENTER, RELIEVER AND ADD ON THERAPY

(from Anil Sir’s Flow Chart only)

1) Intermittent Reliever Therapy

Inhaled SBA (Salbutamol, Terbutaline)
As required
Those needing more than 1 inhaler per month next Step

2) Regular Preventer Therapy

Low dose ICS
If using SABA 3 times week or more
Symptomatic 3 times a week or more
Waking up in night due to asthma at least once a week
 Asthma attack in last 2 years
ICS (Beclomethasone, budesonide, fluticasone) 200 mg twice daily
SABA as required
If still uncontrolled next step

3) Initial add on therapy

Leukotriene receptor antagonist (Montelukast)
LABA and low dose ICS
As fixed dose formulations (Salmeterol / Fluticasone or Formoterol / Budesonide)
[Fixed dose ICS / LABA] with SABA[salbutamol] as reliever
Or MART- Maintenance and Reliever Therapy
If still not controlled next step

4) Additional controller therapy

Increase ICS doses (to moderate or high)
With SABA as reliever
Inhaled Tiotropium Bromide (LAMA)
SR Theophylline

A 25 year old man presents to the outpatient department with a history of day time wheezing and
nocturnal cough for the past four months. His examination was clinically normal and a diagnosis of
mild persistent asthma is made.
Describe the drug management of this patient. (30 marks)

As this patient is having daytime wheezing and nocturnal cough step 3 management is given.

It includes
● Low dose ICS +LABA as preventers daily
● SABA (SOS)
Asthma is a chronic reversible airflow obstruction due to airway hyper responsiveness and bronchial
inflammation. This finally causes airflow limitation.
● ICS is a preventative of asthma as it suppresses inflammation.
● It inhibits the production of inflammatory cytokines, reduce bronchial hyperreactivity
● To reduce the frequency of asthma exacerbation and potentiate the effects of beta receptor
agonist.
● Usually it combines with a LABA
● LABA acts as a preventer and a reliever.
● Beta 2 adrenergic receptor stimulation at airway SM cells causes
- Relaxation of smooth muscle
- Inhibition of release of Bronchoconstrictors from mast cells
- Inhibit microvascular leakage and increase mucociliary transport.
● SABA also has the same effect as LABA.But it occurs faster.
● Usually SABA is taken before taking ICS as bronchodilation increases the transportation of ICS.

Give reasons for the selection of drugs mentioned in 1.1(10 marks)

According to the GINA guidelines for asthma, if symptoms,
● Seen most of the days or
● Wake at the night >= once a week, treated using step 3 management plan

A 26 yr old woman with asthma is on Beclometasone 200 micrograms BD and Salbutamol 200
micrograms PRN, both via a dry powder inhaler. During the preceding months she has suffered
frequent episodes of SOB and wheezing which responded to inhaled Salbutamol. She has also
experienced nocturnal symptoms 2-3 times per week.

What further details would you elicit with regard to her drug therapy?
The inhaler technique should be checked
Whether she is taking ICS daily as prescribed or just using it with SABA for SOS

What modification would you suggest regarding her drug therapy?

Increasing use of SABA or use >2 days per week for symptom relief generally indicates inadequate
control and the need to step up treatment. So as the next step with the use of the same dose of ICS we
can introduce LABA.

Explain the pharmacological basis for the modifications.

The addition of LABA (salmeterol or formoterol) to the treatment of patients who require more than
low-dose inhaled corticosteroid (ICS) alone to control asthma improves lung function, decreases
symptoms, and reduces exacerbations and use of short-acting beta2-agonists (SABA) for quick relief in
most patients to a greater extent than doubling the dose of ICS. LABAs should not be used as
monotherapy for long-term control. Even though symptoms may improve significantly, it is important to
keep taking PICS while taking LABA because LABA can mask the underlying inflammatory condition thus
predisposing to severe exacerbations. Salmeterol is available in a single formulated combination with the
corticosteroid fluticasone.

6 months later she presented to the ETU with an acute exacerbation which was diagnosed as acute
severe asthma. Her SpO2 is 92% on room air.

List 4 therapeutic agents with route of administration, which would administer in the immediate
management of this patient.
● Oxygen to maintain SpO2 94-98% - via nasal cannula or face mask
● Salbutamol 5 mg + ipratropium 0.5 mg via MDI with spacer (better)/ oxygen-driven nebuliser
● Prednisolone 40-50 mg orally or IV hydrocortisone 100 mg
Clinical evaluation an hour after the initial presentation reveals that the patient still has features of
severe asthma.

What is the drug that is indicated now? State the precautions you need to take when administering
these drugs.

Consider IV magnesium sulfate 1.2-2 g infusion over 20 minutes

Magnesium sulfate is a tocolytic agent which has a wide distribution in the body.

Precautions –
 ● Be cautious in severe renal impairment because it is excreted by the kidney and accumulation
has serious side effects.
● C/I in heart block or myocardial damage
● IV administration should be a slow infusion by a constant infusion pump if possible. Rapid
infusions have deleterious effects as MgSO4 is a cardiac and respiratory depressant.
● Monitor the BP of the patient as hypotension is a serious side effect of the drug
● Be prepared with an antidote for magnesium toxicity as calcium gluconate for IV infusion if
needed

Write a discharge prescription for this patient.

● High dose of ICS + LABA
● SABA for SOS
● Oral prednisolone

A 50 year old man on atenolol 50mg daily for hypertension was admitted and treated for acute severe
asthma. He had no previous history of asthma. On discharge his asthma was graded as moderately
severe (Stage 3). He also complained of sleeplessness due to cough Following is his discharge
prescription
● Prednisolone 30mg in the morning
● Salmeterol 25 micrograms /fluticasone 250 micrograms twice daily as MDI
● Erythromycin 250mg 6 hourly
● Theophylline SR 300 mg twice daily
● Montelukast 10mg at night Atenolol 50mg in the morning
● Diazepam 5mg at night

List the drugs that can cause interactions in the above prescription (20 marks)
● Erythromycin-Theophylline/Diazepam
● Atenolol- Theophylline/Diazepam
● Prednisolone - Theophylline/Diazepam

List 3 medicines that should be omitted or replaced, giving reasons. (30 marks)
● Theophylline- Not needed for stage 3 Asthma management
● Atenolol should be changed to a CCB -As Beta blocker causes bronchoconstriction
 ● Prednisolone-Not needed for long term management

Name a reliever medication you would prescribe with its route of administration.(10 marks)
Salbutamol - Inhalation

A 5 year old boy who was having recurrent episodes of wheezing was brought to the hospital with
wheezing and worsening difficulty in breathing. His SpO2 on admission was 90% and rhonchi were
there on auscultation.

List the drugs that you would consider as the initial management along with mode of administration.
● Oxygen via face mask/nasal prongs to achieve SpO2 94-98%
● Nebulised β2 agonist: salbutamol 2.5 mg plus ipratropium bromide 0.25 mg nebulised
● Oral prednisolone 20mg or IV hydrocortisone 4 mg/ kg if vomiting
● Consider adding 150 mg MgSo4 to each β2 agonist/ ipratropium nebuliser in first hour

Discuss the pharmacological basis on using the drugs you mentioned in 3.1.
Muscarinic receptor antagonists, such as ipratropium bromide, prevent cholinergic nerve-induced
bronchoconstriction and mucus secretion. High doses of short-acting anticholinergics may be given by
nebulizer in treating acute severe asthma but should only be given following β2-agonists, as they have a
slower onset of bronchodilation. But when given together they are additive and give prompt relief.

Corticosteroids are anti-inflammatory and systemic administration is done in acute asthma attacks and
that ensures speed resolution of symptoms and reduces the relapse episodes after acute attack.

MgSO4 is a tocolytic agent and thus relaxes smooth muscle in severe

asthmatics.

Discuss the long term drug management on discharge and pharmacological basis for its use.
 ● High-dose ICS
● LABA
● oral corticosteroids
or
● High dose ICS + either LTRA or theophylline + oral corticosteroid

Name a reliever medication you would prescribe with its route of administration (10m)
Salbutamol (5) –Inhalation (5)

List three (3) drugs you would prescribe on discharge, indicating the route of administration of each.
(15 marks)
Prednisolone -- Oral (5)
Salbutamol – Inhalation via MDI (5)
Beclomethasone – Inhalation by MDI (5)

Briefly outline why Formoterol is better than Salmeterol in management of chronic asthma (15m)

Both Salmeterol and formoterol are long acting beta 2 selective agonists. (3) Both of them have a longer
duration of action of more than 12 hours. (2) The longer duration is a result of lipid solubility (1)
Both of them have a high lipid solubility but a higher proportion of formoterol is retained in the extra-
cellular space. (1) The result is a rapid diffusion of formoterol to beta2 receptors and a fast onset of
effect. (2) Salmeterol diffuses more slowly through lipid regions and its onset of action is delayed. (2)
So formoterol has a quicker onset of action thus results in bronchodilation within minutes of inhalation.
(1) Therefore formoterol can be given in acute attacks of asthma and as maintenance therapy in chronic
asthma to prevent further attacks. (2) But due to the late onset salmeterol is not effective in acute
asthma attacks (1)

Discuss the differences in maintenance therapy and management of acute exacerbation of COPD when
compared to that of bronchial asthma.
COPD Asthma

Mainstays for Rx - SABA / Muscarinic antagonists given alone Initiated with inhaled bronchodilators and ICS.
or with steroids Followed up depending on severity and compliance

SABA used when required as initial empirical treatment In addition SABA is also used as an SOS agent

LAMA (tiotropium) / LABA combination provides best quality LAMA is not used for stable asthma
of life with SABA

ICS isn’t routinely prescribed due to S/E (pneumonia and ICS is the cornerstone of treatment
systemic)

LABA / ICS offer inhaled triple therapy

Vaccination and additional antibiotics needed for pneumonia Not needed

and influenza

Mucolytic drugs needed Not needed

Acute Exacerbation of COPD Acute Exacerbation of Asthma

B2 agonist + Ipratropium Bromide via nebulizers SABA

driven by compressed air

Short course systemic corticosteroid Short course systemic corticosteroid

(not long due to excessive S/E)

Antibiotics Not needed

Risk of T2RF (Oxygen kept minimum) Oxygen is SpO2 < 95 percent

MENTAL HEALTH AND MEDICOLEGAL MODULES

Mental Health Module

Categorize antidepressants according to their mechanisms of actions giving examples for each.

Reuptake Inhibitors
 Noradrenaline And serotonin
TCAs – Amitriptyline, Imipramine
SNRIs – Venlafaxine
Serotonin only –
SSRIs – Fluoxetine, Paroxetine, Sertraline, Citalopram
Noradrenalin only –
Reboxetine

Auto Receptor Inhibitors

Noradrenaline And Serotonin
Mirtazapine

Enzyme Inhibitors
Noradrenaline And Serotonin
Monoamine oxidases – Phenelzine , Moclobemide

List clinical uses of the above drugs you mentioned.

Depression
Anxiety disorders – Panic disorders, Generalized anxiety disorder
Eating disorders – Bulimia nervosa (Not anorexia nervosa)
Neuropathic pain – TCA, SNRI
Nocturnal enuresis of children – TCA
Migraine prophylaxis – TCA

Mention possible side effects for each type stating a possible mechanism.

For all – Hyponatraemia / Increased suicidal thoughts (sp. Children and Young adults)

TCA
● Alpha Blockage – QT prolongation, Postural hypotension
● Antimuscarinic – Dry mouth, Urinary retention, Blurred vision, Constipation
● Histamine block – Weight gain, Sedation
 ● Lower seizure threshold
● Serotonin elevation – Sexual dysfunction
SSRI
● GI effects – Nausea, Vomiting, Anorexia
● Dizziness
● Sleep disturbances
● Akathisia
● Sexual dysfunction
● Agitation
● Suicidal thoughts are more common
MAO
● Histamine block – Sedation, Weight gain
● Serotonin retention – Sexual dysfunction
● Postural Hypotension
● Insomnia
● Ataxia
● Hypertensive reactions – Increased catecholamine at adrenergic nerve endings – Increased
absorption of sympathomimetics from the gut due to reduced activity of MAO in the gut and
liver.

Because gastro-intestinal monoamine oxidase (MAO) effectively prevents dietary pressor amines,
typically tyramine, from entering the tissues, a marked hypertensive response (the "cheese reaction")
can occur when subjects treated with antidepressant MAO inhibitors ingest foods or beverages rich in
such amines.

Name the antidepressant drugs that can cause sexual dysfunction

- SSRI
- TCA
- MOAI
- SNRI – Specially Duloxetine

Name main categories of antipsychotics.

- Traditional
 - Atypical

Compare and contrast the side effects of two main categories.

What are the depot preparations given in psychosis?
- Flupentixol Decanoate
- Fluphenazine Decanoate
- Haloperidol

Mention sedative and non-sedative drugs in each of two main categories.

- Atypical drugs (Newer) are not usually sedative as they minimally act on histamine receptors.
- Among typical drugs – Chlorpromazine is mostly sedative
- Sulpiride is also quite sedating.
- Less sedating -Flupentixol, Pimozide

Describe the pharmacological basis for the development of serotonin syndrome when fluoxetine is
given to a patient who is on tramadol (20 marks)

Serotonin syndrome is a life-threatening condition with symptoms including hyperthermia, agitation,

tremors, hypertension etc. caused by increased serotonergic activity in the CNS.

Fluoxetine is a Selective Serotonin Reuptake Inhibitor (SSRI) which acts by inhibiting the serotonin
reuptake, thus increasing the serotonergic activity.

Fluoxetine is also an inhibitor of hepatic cytochrome enzymes which are involved in metabolization of a
number of drugs including tramadol.

Tramadol is a centrally acting analgesic with relatively weak µ-opioid receptor activity. However, it also
inhibits neuronal reuptake of norepinephrine and enhances serotonin release.

Therefore, co administration of tramadol and fluoxetine results in an adverse drug interaction resulting
in a buildup of unmetabolized tramadol.
Drug interactions due to enzyme inhibition occur rapidly. As a result, both drugs cause a hyper
serotonergic state inducing serotonin syndrome.

Describe the mechanism of action of benzodiazepines. (35 marks)

Benzodiazepines is used as a (1)

- Hypnotic
- Anxiolytic
- Muscle relaxant
- Anti-convulsant

Allosteric activator of GABA receptor in neuronal membranes widely distributed in the CNS. (2)
GABA receptor functions as a chlorides ion channel
and it is activated by the inhibitory neurotransmitter GABA (1)

GABA is the most important inhibitory neurotransmitter in the CNS. (1)

Controls the state of neuronal excitability in all brain areas like cerebral cortex, spinal cord,
hypothalamus SN etc. (1)

Balance between excitatory inputs and inhibitory GABAergic activity determines neuronal activity. If the
balance swings in favor of GABA, then sedation, amnesia, muscle relaxation and ataxia appears and
nervousness and anxiety are reduced. (2)

When GABA binds to GABA receptor, allows more chloride ions into the neuron and decreasing
excitability. (2)

Benzodiazepines are not true agonists. Therefore, GABA needs to be present for benzodiazepine effects
to be detectable. (2)
In the presence of GABA
● Benzodiazepines bind to allosteric site (1) of the receptor
● Causes a conformational change in the receptor
● So that the Gamma amino butyric acid can bind to the receptor more efficiently.

Enhance effectiveness of GABA to producing a larger inhibitory effect by increasing the frequency of the
chloride ion channel opening (1)

Increasing the inhibitory effect of GABA on neuronal excitability by resulting in membrane

hyperpolarization (1)

Name two (2) benzodiazepines. (05 marks)

● Alprazolam
● Chlordiazepoxide
● Clonazepam
● Diazepam
● Estazolam
● Lorazepam
● Midazolam
● Oxazepam

List three (3) clinical indications for the use of benzodiazepines. (15 marks)
● Anxiety relief
● Insomnia and sedation during surgical procedures
● For treatment of epilepsy and seizure states
● As a component of balanced anesthesia (Intravenous administration)
● For control of ethanol and other sedative-hypnotic withdrawal states.
● For muscle relaxation in specific neuromuscular disorders
● As diagnostic aids or for treatment in psychiatry
Briefly describe what advice you would give a patient who is prescribed an oral benzodiazepine. (20
marks)
● Educated regarding duration and dose of the drug
Due to risk of dependance
● Don’t stop abruptly as there can be a rebound of symptoms.
Benzodiazepines are associated with withdrawal syndrome.
● Educate regarding adverse effects (Sedation, amnesia and impaired psychomotor function can be
hazardous with driving vehicles, operating machinery)
Perceptual disorders eg : hallucinations, Headache, giddiness, alimentary tract upset, skin rashes
and reduced libido.
● If female, ask about current and future pregnancy wishes and whether she's a lactating mother.
(cross the placenta and cause fetal cardiac arrhythmia, muscular hypotonia)
● Always tell to inform the doctor that he's on benzodiazepines (interactions with other centrally
acting depressant drugs, H1 receptor antihistamines) and (increasing benzodiazepine
concentration with drugs that slow metabolism by enzyme inhibition and lowering of plasma
concentration with enzyme inhibitors).
● Blood pressure should be monitored if the patient has been co-prescribed antihypertensive
drugs and vasodilators as interacting with those drugs can cause unexpected hypotension
● Avoid alcohol and other sedative medication

Briefly explain how diazepam is effective in the treatment of insomnia (20 marks)

Diazepam is a benzodiazepine. Benzodiazepines are agonists at the

GABA receptors. They attach to a specific site on the GABA receptors, attached to the chloride channel
complex and potentiate the effect of GABA. GABA acts by opening chloride channels into cells. GABA
controls the state of neuronal excitability and is the most important inhibitory neurotransmitter in the
CNS.

Due to its GABA agonist action which is inhibitory on the reticular activating system and hypothalamus
which controls the sleep wake cycles, benzodiazepines have hypnotic and sedative actions.

Choice of a benzodiazepine as a hypnotic is determined by its pharmacokinetic properties.

Benzodiazepines are effective after oral administration and are metabolized in the liver. After
metabolism diazepam gets converted to an active metabolite which has a long half-life (80 hours).

Therefore, effective drug concentrations will be maintained throughout the night, greatly extending the
duration of drug action.

This is important to minimize waking from sleep at night. Diazepam also has a rapid onset of action
therefore it induces sleep without a delay to improve sleep in insomnia. Therefore, it can be taken at
night as an effective medication in the treatment of insomnia.

Compare and contrast the first generation (typical) antipsychotics with second generation (atypical)
antipsychotics with regard to site of action, clinical uses and adverse effects. (30 marks)

Typical Antipsychotics Atypical Antipsychotics

Older drugs Newer drugs

Block mainly DA Blocks DA and 5HT

Mainly D2 receptors D2 + D4 + 5HT

Treats (+) symptoms Treats (+) and (-) symptoms

Similar efficacy Similar efficacy

More adverse effects Less adverse effects

Useful in refractory disease Less useful

More withdrawal symptoms Less withdrawal symptoms

Higher Extrapyramidal side effects Lesser

Higher risk of tardive dyskinesia Lower risk

Higher risk of prolactinemia Lower risk

Lower risk Higher risk of metabolic side effects

Lower risk Higher risk of weight gain, Sexual dysfunction and

 diabetes

Eg- Haloperidol Eg- Clozapine

Chlorpromazine Risperidone
Olanzapine
Quetiapine
Aripiprazole

Briefly describe the neuroleptic malignant syndrome regarding antipsychotic drugs.

Neuroleptic malignant syndrome is a rare but fatal outcome of the antipsychotic drugs.
It is characterized by,
● Hyperthermia
● Fluctuating consciousness
● Muscle rigidity
● Autonomic dysfunction
● Tachycardia
● Labile blood pressure
● Sweating and urinary incontinence
Essential to discontinue the antipsychotic drugs.
There is no proven medication for the condition.

But medications like bromocriptine, Dentrolene may help the symptoms.

Cooling of the patients is done to help the symptoms.

Name two anti-psychotic drugs that cause agranulocytosis

Clozapine
Chlorpromazine

Name the traditional drugs that cause movement disorders.

Haloperidol
Fluphenazine, Perphenazine, Trifluoperazine.

List 5 side effects of typical antipsychotic drugs

● Extrapyramidal effects - Movement disorders, Parkinsonism, Akathisia, Dystonia, Dyskinesia,
Tardive dyskinesia
● Endocrine effects - Gynaecomastia, Galactorrhoea, Menstrual irregularities, Impotence, Weight
gain
● Autonomic side effects - Anticholinergic effects , Dry mouth, Blurred vision, Difficulty with
micturition, Constipation
● Psychological effects - Impaired performance, Sedation
● Cardiotoxicity
● Blood dyscrasias

Medicolegal Module

Atropine is indicated in the treatment of severe bradycardia following acute yellow oleander poisoning
(25 marks)

Yellow Oleander seed contains highly toxic cardiac glycosides A and B and neriifolin
Mechanism of toxicity

1) Increased inotropy and increased myocardial automaticity

● Cardiac glycosides bind to and inactivate the Na+/K+ ATPase pump on the cytoplasmic
membrane of cardiac cells
● As a result, intracellular Na+ concentration increases
● This affects the Na+/ Ca+ exchange channels resulting in an increase in intracellular Ca+ that
leads to
a) Increased force of contraction
b) Increased Myocardial automaticity (Raises the resting membrane potential of the cell,
leading to increasing rates of spontaneous cellular depolarization)
2) Reduced heart rate

● Indirectly enhance vagal activity by central and peripheral mechanisms, resulting in reduced
conduction through AV and SA nodes

Atropine is an antimuscarinic anticholinergic drug

that selectively and reversibly blocks central and peripheral muscarinic receptors.

Acts equally on M1, M2 and M3 receptors.

It antagonizes the muscarinic receptors at the peripheral synapses of the vagal nerve and eventually
corrects the bradycardia caused by enhanced vagal activity.

Digoxin specific antibody fragments can be used as the antidote

Describe the use of atropine in acute OP poisoning.

OP poisoning occurs due to the repetitive and exaggerated stimulation of nicotinic and muscarinic
receptors, which causes increased parasympathetic effects.

At the neuromuscular junction (muscarinic) and cholinergic receptors, acetylcholine is the

neurotransmitter which is stored in vesicles in the presynaptic terminals.
When the nerve or muscles are stimulated
- Voltage gated + channels are stimulated
- Ca+ influx occurs
- Stimulates the release of Ach from the vesicles.

Ach diffuses through the Synaptic Cleft and binds with the postsynaptic receptors.
Once bound,the receptors are stimulated.

Once stimulated
- Post synaptic impulse transmission
- And due to abundance of Ach Esterase enzymes occurs in the cleft
- Break down the bound Ach.

This is important for the effective transmission and muscle contraction, because then another Ach can
bind to the same receptor. The receptors can be stimulated at a constant frequency.

In OP poisoning
- Irreversible inhibition of Ach Esterase
- Accumulation of Ach in the synaptic cleft.

Therefore, bound Ach will not be removed, causing overstimulation of these sites, giving rise to the
clinical effects of OP poisoning (increased saliva and tear production, diarrhea, nausea, vomiting, small
pupils, sweating, muscle tremors, and confusion)

Atropine is a competitive muscarinic antagonist.

- Bind to the muscarinic receptors
- Preventing Ach from binding
- No excessive stimulation of the receptors
Therefore the clinical features subside.

A 25 year old woman (weight 50kg) is admitted following ingestion of 15 tablets of 500mg
Paracetamol 3 hours ago. She has vomiting and mild upper abdominal pain.
Name one (1) antidote that is indicated and state the mode of transmission. (05 marks)
N-acetyl cysteine (NAC) – Intravenous

Describe the pharmacological basis for the use of the antidote you mentioned above in acute
Paracetamol poisoning. (35 marks)

When Paracetamol is consumed in therapeutic doses, it undergoes metabolism largely through

conjugation with sulfate and glucuronide up to 90% of the dose.

The remaining drug produces a highly toxic metabolite – NAPQI which is later bound to the sulfhydryl
groups of glutathione and excreted from the body.

When it is taken in high dose the capacity to conjugate with the sulfhydryl groups is exceeded and large
amounts go in the oxidative pathway and produce NABQI.

Therefore the glutathione levels to bind with NABQI are depleted and the NABQI starts to bind with
other sulfhydryl groups of the body in live and the kidney causes harm to the respective organs.

NAC is a precursor of glutathione synthesis and it replenished hepatic glutathione stores.

When NAC is administered to a patient with acute Paracetamol poisoning, glutathione and NAC itself
binds to reactive toxic metabolites, preventing it from acting on hepatocytes.

NAC also provides an additional advantage of scavenging the reactive oxygen species and additional NAC
will increase the hepatic perfusion.

Therefore NAC improves the patient’s outcome even with encephalopathy.

NAC is usually given only when the patient is symptomatic. If not usually methionine given.

When NAC is given within 8 hours of the poisoning it provide near complete protection and when
administered after 8 hours it offers mortality benefit but incomplete protection of the hepatotoxicity,
State one (1) side effect that could occur with the antidote you mentioned in 3.2.1. (05 marks)
Anaphylactoid reaction

Outline The Management Of Acute Paracetamol Poisoning

Antidotes recommended if an adult has ingested a single overdose of

● >150 mg/kg or >10g
● Most effective if started within 8 hours but still effective even later

Oral Methionine or IV N-acetylcysteine is used

● On admission, the patient is given activated charcoal to prevent further absorption

If the patient presented within 8 hours of poisoning with no symptoms like vomiting > Oral Methionine is
used
If the same patient found to have elevated transaminase subsequently, switch onto > NAC

If the patient presents within 8 hours of poisoning with symptoms like vomiting or having risk factors
- IV NAC has to be administered.

If the patient anyway presents after 8 hours of poisoning, NAC has to be started soon.

● NAC is given together with 5% dextrose

NAC is a drug known to cause dose related anaphylactic reactions due to histamine release (in 15% of
patients receiving NAC). Commonly occurs within 1 hour of starting the infusion.

The anaphylactoid reaction can be managed with temporarily discontinuing or slowing the infusion (can
recommence it once the reaction settled) or
By administering an antihistamine which is rarely required
NAC should be continued once commenced except during anaphylaxis or hypersensitivity reactions.

Reliable paracetamol levels in plasma falls below the treatment line for the patient

After the regime, blood for PT/INR and basic LFT should be done
If liver function or coagulopathy develops, an infusion should be maintained until INR falls < 2. (4*15
points)

Describe the mechanism of toxicity of acute paracetamol poisoning. (20 marks)

When paracetamol is taken in normal therapeutic doses, most of them (1) is converted into nontoxic
metabolite (1) by conjugation (1) in the liver (1).

Small amount is oxidized via cytochrome P450 (2) pathway and will result in a toxic
compound(N-acetyl-p-benzoquinoneimine) which is detoxified by binding to sulfhydryl groups of
glutathione. (2)

Toxic dose of paracetamol is considered as being>150 mg/kg and considered as hepatotoxic (1)

In case of paracetamol overdose, the conjugation pathway becomes saturated (2) and more paracetamol
is shunted into cytochrome P450 to produce toxic metabolites. (2)

After 8 hours of significant overdose glutathione get depleted (1) as demand for glutathione is higher
than its regeneration. (1)

Therefore, toxic metabolite binds to SH groups in phospholipid membranes (1) and tissue protein causing
disruption of cell membrane. (1) It damages the liver, kidney, pancreas and heart. (1)
Toxic Dose Of Paracetamol Is considered as being >150 mg/kg and considered as hepatotoxic. Normally
when paracetamol is ingested, most of it will be conjugated by the liver and only small percentage (15%)
will undergo metabolism under cytochrome P450 pathway and will result in a toxic compound
(N-acetyl-p-benzoquinoneimine)

The toxic compound will be detoxified by the sulfhydryl groups of glutathione under normal
circumstances. But,during overdose, the percentage of paracetamol undergoing cytochrome P450

Will be comparatively higher and after 8 hours of significant overdose, glutathione stores will be
depleted.

This toxic metabolite will bind to sulfhydryl groups in phospholipid membranes and tissue proteins

Resulting In Disruption Of Cell Membranes

This will occur in the kidney, heart and pancreas in addition to the liver causing organ damage. (5*6
points)

Methanol Poisoning
Methanol is converted by alcohol dehydrogenase enzyme
Into Formaldehyde
That then gets converted by the aldehyde dehydrogenase
Into Formic Acid

Formic Acid inhibits mitochondrial cytochrome oxidase activity

Preventing oxidative metabolism
Producing “Tissue Hypoxia“

Antidote is Ethanol
Competes with methanol for alcohol and aldehyde dehydrogenase
Preventing the formation of formaldehyde and formic acid

Iron Poisoning
When serum iron conc exceeds the iron binding capacity of transferrin after blood
Free circulating iron damages many free organs by direct cellular toxicity
Antidote - Desferrioxamine

A 25 year old woman (weight 50 kg) is admitted following ingestion of 15 tablets of 500mg
paracetamol 3 hours ago. She has vomiting and mild upper abdominal pain.

Name one (1) antidote that is indicated and state the mode of administration (05 marks)
N-acetylcysteine (NAC) Intravenous route

Describe the pharmacological basis for the use of the antidote you mentioned in 2.2.1 in acute
paracetamol poisoning. (35 marks)
● When Paracetamol is consumed in therapeutic doses, it undergoes metabolism largely through
conjugation with sulfate and glucuronide up to 90% of the dose.
● The remaining drug produces a highly toxic metabolite - NAPQI which is later bound to the
sulfhydryl groups of glutathione and excreted from the body. When it is taken in high dose the
capacity to conjugate with the sulfhydryl groups is exceeded and large amounts go in the
oxidative pathway and produce NABQI.
● Therefore the glutathione levels to bind with NABQI are depleted and the NABQI starts to bind
with other sulfhydryl groups of the body in live and the kidney causes harm to the respective
organs. (10 marks for toxicity)
● NAC is a
a) Precursor of glutathione synthesis (2) and
b) Source of sulfhydryl groups (2)

● When NAC is administered to a patient with acute Paracetamol poisoning,

a) It replenish the glutathione source (2)
b) allows intermediate toxic metabolite to be conjugated to non toxic metabolites (2)
● NAC also provides Secondary benefits as an antioxidant by preventing lipid peroxidation(2) and
acts as a free radical scavenger(2)
Therefore NAC improves the patient's outcome even with encephalopathy. NAC is usually given only
when the patient is symptomatic. (1)
When NAC is given within 8 hours of the poisoning it provides near complete protection and when
administered after 8 hours it offers mortality benefit but incomplete protection of the hepatotoxicity (2)

28th Batch Paper

(1)
1.1) A 60 year old woman presented to the ETU following acute aspirin poisoning. She was treated
with intravenous NaHCO3. Using your knowledge of pharmacokinetics describe the pharmacological
basis for the use of NaHCO3 in this patient. (30 marks)

(Read the past paper answer on NaHCO3 in Aspirin overdose)

1.2) A 78 year old man with bone metastasis following a rectal carcinoma is treated with oral
morphine for pain relief. He frequently needs escalating doses of morphine. Applying your knowledge
on the principles of pharmacodynamics describe the pharmacological basis for the need for frequent
escalations in the doses of morphine. (20 marks)

(Read the essay on tolerance)

1.3) A 62 year old diabetic woman on atorvastatin 40 mg nocte for the last two years recently
diagnosed with statin induced muscle toxicity. She was treated with the following drugs for a
moderate community acquired pneumonia recently.
- Clarithromycin 500 mg bd
- Amoxicillin - Clavulanic acid 625 mg bd
- Salbutamol MDI 200 ug 2 puffs bd
Describe the basis for the occurrence of muscle toxicity in this patient (30 marks)

(Read the essay on drug interactions. Since Clarythromycin is an hepatic enzyme inhibitor and statins are
metabolized in the liver. The side effect of statin toxicity is muscle toxicity)

1.4) A 3 day old baby was diagnosed with neonatal sepsis and the treatment regimen included IV C
penicillin 50 mg/kg every 12 hours. Using your knowledge on pharmacokinetics explain the reasons for
twice daily dosing compared to standard dosing frequency. (20 marks)

(2)
2.1)
A 63 year old woman with hypertension, hyperlipidemia, CKD (eGFR 30ml/min) and ischemic heart
disease was treated for acute congestive heart failure. On discharge she was hemodynamically stable
with a blood pressure of 140/90 mmHg. There was mild pitting edema and fine crepitations in lung
bases. Her blood investigations revealed serum potassium of 5.8 mmol/l (3.6 to 5.2)

In addition to a diuretic she was discharged on the following medication

● Losartan 50 mg nocte
● Bisoprolol 2.5 mg bd
● Atorvastatin 20 mg nocte
● Aspirin 75 mg nocte
2.1.1) State the preferred diuretic out of furosemide and hydrochlorothiazide you would recommend
for this patient giving reasons for your recommendations (20 marks)

B/L Fine crepitations in lung bases = Pulmonary edema

Needed urgent symptomatic relief
PE is an indication for loop diuretics
The other indication is mild hyperkalemia
(Read the chart on diuretics or the essay of furosemide in CCF)

2.1.2) State whether you would agree or disagree with the decision to prescribe each of the four drugs
mentioned above other than diuretics. Explain your answer giving reasons for each drug. (40 marks)

2.2)
A 64 year old man presented with chronic cough, loss of weight and hemoptysis. He was diagnosed to
have primary pulmonary TB. He commenced on the intensive phase of the anti TB treatment regimen
according to the SL guidelines.
2.2.1) One month later the patient presented with numbness and tingling of the extremities and was
diagnosed to have peripheral neuropathy. State the likely drug responsible giving reasons. (20 marks)

2.2.2) List two major adverse effects of anti tuberculous drugs which require his drugs to be stopped
and referred to a specialist center.
In each instance state the drug responsible for the respective adverse effect. (20 marks)

(3)
3.1)
A 25 year old man presented to a general practitioner with nocturnal wheezing and cough on most
days of the week for the past two months. Auscultation revealed rhonchi in both lung fields. He was
diagnosed as having asthma. He started on Budesonide/ Formoterol metered dose inhaler 160/4.5
mcg twice a day and was advised to take the same inhaler when required to relieve his symptomps.

3.1.1) Explain the pharmacological basis for prescribing the same inhaler as preventer and reliever
therapy of symptoms. (30 marks)

MART = One inhaler for both functions

As it contains a standard predetermined amount of
both Budesonide (Maintenance) and Formoterol (Reliever)

3.1.2) Explain why salbutamol and salmeterol are not suitable as B agonists in MART. (20 marks)

SABA - Duration of action is too short. Need to keep airways open for a longer duration
Salmeterol - Slower onset of action. Formoterol is rapid despite being LABA
3.2) A 66 year old woman with a history of IHD presented with low mood, lethargy and increased
sleepiness. She has a history of overdose of prescription medications. After excluding other
comorbidities a diagnosis of depression was made. She started on fluoxetine 20 mg in the
morning.Outline the reason to justify selecting fluoxetine over a TCA in this patient. (15 marks)
Fluoxetine - SSRI - Does not bind aggressively to other receptors (muscarinic, histamine)
Well tolerated in overdose (as she has a history of overdose)
Less interaction with IHD medication
Fluoxetine could be lethal in overdose
(Cardiac S/E leading to death)

3.3)
3.3.1) Patients with HIV infections are placed on a highly active antiretroviral treatment combination.
List 3 classes of antiretroviral drugs used for the treatment of HIV infections. (15 marks)
3.3.2) List 4 therapeutic objectives in treating patients with HIV infections (20 marks)

Notes

Histamine Receptors

H1
- Arteriolar Dilation, Increased permeability
- Itch and pain in nerve endings
- Appetite and satiety

H2
- Increased force of contraction of heart
 - Increased gastric acid secretion

H3
- Modulate neurotransmitter release
- Appetite and satiety

Effects of Acetylcholine

● Parasympathetic Effects
- Eye (miosis and ciliary muscle spasm)
- Secretions from exocrine glands
- Bradycardia with AV block
- Bronchoconstriction and mucosal hypersecretion
- Mobility of gut
- Contraction of bladder and ureters

● NMJ impulse transmission

● Stimulation of CNS followed by depression
● Vasodilation

Adrenergic Receptors

● A1
- Vasoconstriction
- Increases arterial resistance and reduces venous capacitance
- Mydriasis
- Urinary continence

● A2
- Aqueous humor outflow from eye
- Inhibits insulin and renin secretion
● B1
- Increases Heart Rate
- Increases contractility
- Lipolysis
- Stimulates release of insulin and renin

● B2
- Vasodilation (Reduce PR)
- Bronchodilation
- K uptake into cells
- Skeletal muscle contraction
- Anti inflammatory action
- Glycogenolysis

● Alpha contracts pregnant uterus while B relaxes it

● Insulin is stimulated by B receptors and inhibited by A2
● Renin is stimulated by B1 and inhibited by A2
 Drug Development

Prescribing in children and the elderly

Newborn / Neonate / Preterm / To;ddler Elderly

Full Term - Increased gastric pH

- Gastric acid secretion begins after birth and increases - Delayed gastric emptying
- Neonatal peristalsis is slow - Reduced intestinal motility
- Fraction of drug absorbed in SI unpredictable - Reduced splanchnic blood flow
- GI enzyme (bile acid, lipase) activity is low - Absorption unaffected

Preterm
 - Gastric acid secretion is slow

Gastric emptying is prolonged in the first day

- Higher percentage of body weight in water - Reduced lean body mass

- Extracellular water is 40 percent (20 in adult) - Reduced body water (water soluble drugs toxic)
(Preterm infants have even more water) - Increased fat as a percentage
(Preterm infants have much less fat than full term infants) - Reduced serum albumin

- Protein binding of the drug is reduced in neonates

- Highly reduced activity of liver enzymes - Reduced activity of liver enzymes

- Higher incidence of liver disease
(phenobarbital can induce early maturation of liver enzymes) - Highly variable hepatic blood flow

- GFR much lower in the first few days - Reduced creatinine clearance (Increased half life)
- Reaches adult value in 6 months - (Serum creatine doesn't rise due to reduced muscle
- Higher than adult value in toddlers mass)
- Reduced respiratory capacity

- Reduced saliva production

- Forgetfulness
- Other comorbidities
- Other drugs

SPECIAL CONSIDERATIONS SPECIAL CONSIDERATIONS

- Calculate dose according to body surface area - ADRs may present as a normal function of age
- Suspensions are heterogeneous and shake before use
- Elixirs are alcoholic and homogeneous (no need a shake)
- Don’t combine with food or milk
 Antiviral Drugs

Drug Action Indications Other important points

Oseltamivir [Tamiflu] Neuraminidase inhibitors Influenza A and B Can be used a prophylaxis

Zanamivir Inhibits neuraminidase enzyme
O - GI S/E so given after food
Prevents spread of virions from Z - RS irritation, avoid in asthma
cell to cell and COPD

Does not affect vaccine

Amantadine Block viral membrane matrix Influenza A Can be used as prophylaxis

Rimantadine protein M2
Inhibitors of viral uncoating

Ribavirin Synthetic Guanosine analog RSV

Chronic Hep C

Interferon alpha Hep B and C Not active orally

HPV (genital warts)

Interferon beta Multiple Sclerosis

Lamivudine Cytosine analogue HIV

HBV

Acyclovir Guanosine analog HSV 1 and 2 (IV only) Known complication is AKI so
Inhibits viral DNA VZV keep hydrated

Distributed well including CSF EBV If given orally take 5 times daily for
7 days

Ganciclovir Analog of acyclovir CMV retinitis and

 prophylaxis

Antifungal Drugs

Name / Class Mechanism of action Important Points

Amphotericin (Polyene) Forms large pores in fungal membrane Gold standard for treating disseminated
(Impairs transport functions, ROS damage) infections caused by Aspergillus and Candida.

Synergy with Flucytosine

Poor oral BA (therefore used to treat gut

infection)

Narrow therapeutic index leading to high

renal toxicity

Nystatin / Fungicidin

Griseofulvin Interferes with mitosis by binding to fungal Systemic administration that treats nail
microtubules infection

Azoles Inhibit the fungal cytochrome P450 3A Broad spectrum

enzyme involved in producing ergosterol
Which is needed for cell wall synthesis Less side effects compared to amphotericin

Inhibits cell replication Ketoconazole has good oral BA

Inhibits hepatic cytochromes

Inhibits adrenal cortex steroid synthesis
(Gynecomastia)
 Ciclosporin and astemizole - Increase
ketoconazole conc

Rifampicin reduced histamine absorption

FLuconazole can be given IV

Flucytosine Affects RNA structure

Immunosuppressants and Immunomodulators

Name / Class Function Other important points

Immunosuppressants Suppresses the immune system

Calcineurin inhibitors Interferes with the activation of T lymphocytes to Cyclosporine

- Cyclosporin release cytokines - Oral or IV
- Tacrolimus Reduced production of interleukin-2 - Metabolized by the P450 3A
Reduced proliferation of T-cells - Significant interpatient variability in
bioavailability
Uses
1) Solid organ transplantation (Prevent Tacrolimus
graft-versus-host (GVH) disease) - Narrow therapeutic window
- Hepatic metabolism
2) Autoimmune diseases, (RA, uveitis, psoriasis, (FLuconazole interaction)
asthma, T1DM)
- Therapeutic drug level monitoring
 3) Prevent restenosis after coronary angioplasty

Corticosteroids Restrain clonal proliferation of Th cells through reducing Adverse effects

transcription of IL-2 gene - Cellular immunity is higher than
humoral

Uses - Cushing’s Syndrome

1) Combination with cytotoxic drugs in treatment - Growth inhibition in children

of specific malignancies (e.g. Hodgkin’s disease, - Suppression of previously produced
acute lymphocytic leukemia) Ab therapy
2) Reduce cerebral oedema in patients with
metastatic or primary brain tumors
(dexamethasone)

Mycophenolate Inhibit purine or pyrimidine synthesis Common adverse effects of

Mofetil Suppress both T and B cell activation immunosuppressants
- Cancer risk

Uses - Other cell lines

1) Transplantations - Metabolic processes

Azathioprine, Inhibit purine or pyrimidine synthesis

Immunomodulators (Immunomodulators don’t suppress the immune system)

Immune Globulin Formed from several donors

Intravenous (IGIV)

Rho(D) Immune Human IgG preparation

Globulin (RhoGAM)

Monoclonal Targeted antibodies Infliximab is targeted against TNF-α

antibodies (MABs) With specificity and high affinity for relevant antigen
Used in Oncology

Interferons Interferon-alfa-2a inhibits cell proliferation

(Leukemia, melanoma, Hep BC, Kaposi sarcoma)

Interferon-beta-1b in multiple sclerosis

Cytokines Treatment of neoplasms

Treatment of hepatitis B and C

Vaccines

Tute Questions

Define the term apparent volume of distribution.

The distribution volume of a drug is the volume in which it appears to

distribute if the concentration throughout the body were equal to that in plasma, i.e. as if the body were
a single compartment.
(Two assumptions made here are the concentration of drug in the body being equal to that of plasma
and the body being a single compartment)

Factors affecting Volume Distribution

Lipid / Water Solubility

Gentamicin is highly ionized and does not cross cell membranes easily and no protein binding (Vd is
close to ECF volume)

Tissue Binding
Digoxin is extensively bound to Na/K ATPases
Vd is very large

Plasma Protein Binding

Extensive Plasma binding leads to a small Vd
Ex- Warfarin

Partitioning of the drug into fat

In obesity Vd of some drugs may increase

Clinical Application of Volume of Distribution

To find the loading dose needed to maintain a target concentration ;

Loading Dose = Vd * Target Concentration

Bioavailability also affects this equation

Bioavailability taken as a percentage should be added

Loading Dose = (Volume of Distribution * Target Concentration) /

Bioavailability

(HINT: Intravenous drugs have a bioavailability of 100% or 1)

To find the Half Life

Half Life = 0.7 * Vd / Clearance

The volume of distribution of theophylline is 0.5 L/kg. Calculate the lV loading dose of theophylline in
a 70kg adult to achieve a plasma concentration of l0 mg/L.

LD = Vd X (Conc/BA)
BA=1 in IV
= 0.5L/kg X [(10 mg/l)/1]

Explain receptor upregulation and downregulation giving examples.

Receptors are protein molecules on the surface of a cell which bind molecules known as ligands. Ligands
can be hormones, drugs or neurotransmitters. On binding of the ligand receptors undergo a
conformational change that brings about a response

Long term exposure to an agonist can lead to a decrease in the number of receptors (Downregulation)
Eg - Prolonged salbutamol administration in asthmatics leads to downregulation
Higher doses are needed over time

Long term exposure to an antagonist lead to formation of new receptors (Upregulation)

Eg - Haloperidol is a D2 antagonist used to treat schizophrenia
Higher doses needed over time or a different drug is used

What is the pharmacological basis of using dobutamine in cardiogenic shock?

Cardiogenic shock - Heart unable to pump blood. Reduced tissue perfusion

Dobutamine is a synthetic catecholamine
Primarily a B1 receptor agonist with some A effects
B1 effects
- Increases HR (SA node stimulation)
- Increases contractility
- Greater inotropic effect over chronotropic
To restore perfusion
Preferred over dopamine since
- Relatively less A effects
- Dopamine causes peripheral vasoconstriction at higher doses due to A1 stimulation
Also has no peripheral effects (Renal)

List 3 anticholinergic drugs used therapeutically and state their clinical indications. -MCQ

Pilocarpine
- Not hydrolyzed by Ach
1) Reduces intraocular pressure in chronic simple / primary open angle glaucoma
- Causes miosis and accomodation
- Facilitate aqueous humor outflow into the canal of Schlemm, which drains the anterior chamber
2) Treat dry mouth following Sjogren’s Syndrome
3) Irradiation of head and neck tumors

Neostigmine
1) Myasthenia Gravis
2) Reversal of action of competitive NMJ blockers
Pyridostigmine
1) Compared to Neostigmine
- Less powerful action
- Slower onset
- Slightly longer duration
- Fewer visceral effects
PREFERRED due to smoother action and less frequent dosage
Atropine
- To dilate the pupil and cause
- Prevents reflex bronchoconstriction and mucosal secretion during anesthesia as premedication
- Reduce involuntary movements and rigidity in Parkinson
- Antidote in acute OP poisoning
- Antispasmodic

Hyoscine
- Antiemetic used to treat motion sickness

Ipratropium Bromide
- Blocks smooth muscle airway constriction
- Increase mucus secretion in response to vagal activity
- Acute asthma
- Chronic COPD

Tiotropium
- Long acting muscarinic bronchodilator
- Management of COPD
Benzhexol
- Treat drug induced parkinsonism

An 18-year-old child who is preparing for an advanced level examination presented with itchy eyes,
rhinorrhoea and sneezing in the morning. He was diagnosed as having allergic rhinitis. List the classes
(generations) of antihistamine group of drugs giving examples which can be used in the treatment of
this patient. Discuss the choice of antihistamine giving reasons for your choice

H1 antihistamines
Gen 1
- Chlorphenamine
 - Diphenhydramine
- Promethazine
Gen 2
- Cetirizine, Loratadine, Terfenadine
Gen 3
- Levocetirizine, Desloratadine, Fexofenadine
H2 antihistamines
- Cimetidine
- Famotidine
- Nizatidine
- Ranitidine
H3 antihistamines
- Pitostilant
H1 antihistamines are inverse agonists. They stabilize the H1 receptor into an inactive state and in doing
so produce the opposite effect to histamine. Reversible competitive binding

Many actions in addition to blockade of the actions of histamine.

Due to the similarity of the general structure to the structure of drugs that have effects at muscarinic
cholinoceptor, α adrenoceptor, serotonin and local anesthetic receptor sites.

Including Sedation (not desired here since he is an AL student)

Second gen H1 antihistamines are relatively selective for H1 receptors
Enter the brain less readily
Lack the unwanted antimuscarinic effects.
Differ in their duration of action

Third gen antihistamines are active metabolites

Having the least adverse effects

Allergic rhinitis in mainly mediated by actions of H1 receptors (SM constriction)

H2 receptors have a minimal place
Pitostilant is an anti H3 that increases wakefulness leading to sedation
A 45 year old man with HtV and chronic liver disease caused by hepatitis C is diagnosed with
cryptococcal meningitis. He was treated with amphotericin B For 2 weeks in the induction phase of
therapy. Fluconazole was started as the consolidation and maintenance therapy. What
pharmacological properties of fluconazole make it a desirable drug in this patient?

Azoles inhibit the fungal cytochrome P450 3A enzyme that is involved in producing ergosterol, which is
needed for cell wall synthesis.

Inhibits cell replication

Broad spectrum
Relatively safe and less side effects compared to amphotericin B
Less inhibition of hepatic steroidogenesis

Good oral bioavailability

Given oral or IV
Long half life 25 hours warrants to less frequent dosing

Good CNS concentrations and in ocular fluids

Eliminates cryptococcus reducing their levels in CS

Outline the principles of drug therapy of HIV infection.

Viruses are dependent upon the host. They do not carry out metabolic processes. Must use the host’s
cells to replicate. Inject their own DNA or RNA into cells that become mini-factories that produce more
viruses. Cells are programmed to rupture and release new viruses into the host to infect more tissue.
Drug therapy is aimed at killing the virus without killing the host cells. Therapy is complicated as the
clinical symptoms appear late in the course of the disease, when most viral particles have replicated.
Antiviral drugs block virus attachment or disrupt transcription or synthesis.

HIV Triple Therapy

Start HIV treatment on
- TWO Nucleoside/Nucleotide Reverse Transcriptase Inhibitors
Combined with either ONE
- Integrase inhibitor
- Non-nucleoside reverse transcriptase inhibitor
- Protease inhibitor – hence, ‘triple therapy’.

Nucleoside reverse transcriptase inhibitors are referred to as the ‘backbone’ of a first-line HIV treatment
combination.Disrupt the construction of a new piece of proviral DNA, thereby stopping the reverse
transcription process
- Abacavir, Didanosine, Lamivudine, Zidovudine

Non Nucleoside reverse transcriptase Inhibitors (NNRTIs). Interfere with the reverse transcriptase
enzyme by binding directly to it, blocking the reverse transcription process.
- Delavirdine, Efavirenz, Etravirine, Nevirapine

Protease inhibitors (PI). Block the activity of the protease enzyme, resulting virions are
immature and unable to infect new cells.
- Atazanavir, Indinavir, Nelfinavir,Ritonavir,Saquinavir

Integrase inhibitor
- Raltegravir

Principles of HIV Therapy

1) Monitor plasma viral load and CD4 count.
2) Start treatment before immunodeficiency becomes evident.
3) ART is recommended for all individuals with HIV regardless of the CD4 count to reduce the
morbidity and mortality and to prevent HIV transmission to sexual partners and infants.
 4) Aim to reduce plasma viral concentration as much as possible for as long as possible.
5) Use combinations of at least three drugs
6) Change to a new regime if plasma viral concentration increases

Post Exposure Prophylaxis (PEP) started within 72 hours (3 days) after a possible exposure to HIV. PEP is a
combination of three drugs. You take them once or twice a day for 28 days.

A 25 year old previously healthy man presents with fever, sore throat, cough and sneezing of 3 days
duration. His wife has influenza A, a week ago. Discuss the place of oseltamivir in this patient.

Oseltamivir is a neuraminidase inhibitor

Brand name Tamiflu
Neuraminidase enzyme is essential for essential for life cycle of influenza viruses
Prevent release of new virions, spread from cell to cell
Effective against type A and B
Does not affect the vaccine

Oseltamivir is orally active

Rapidly metabolized in liver to active form
A/E include nausea and vomiting so give after food

Reduction of viral load in body

Reduces symptoms and improves outcome
Can be used to treat the wife’s influenza and prevent spread of influenza to household

Describe what precautions you would take when administering intravenous benzylpenicillin to a
patient?

1) Patients should not have a history of adverse effects to Penicillin or to multiple other allergies.
(Allergic symptoms include itch, rash, fever, angioedema)
 2) Contra-indicated in patients allergic to peanuts or soya (benzylpenicillin contains phospholipids
from soya lecithin). (Patients should be monitored for 30 minutes for hypersensitivity reactions
following the injection)

3) Drug list should be modified if any interactions are present with other drugs the patient is using.
Ex- Methotrexate, Phenindione, Leflunamide, Coumarins. Cross allergy occurs among multiple
forms of penicillins. This should be taken into consideration.

4) Caution drug usage in hepatorenal disease, due to delayed metabolism and excretion. This could
lead to toxicity of the drug.

5) If Benzylpenicillin Sodium is given, sodium could accumulate in patients with renal failure. High
doses may cause neurotoxicity.

6) Monitor infants being breastfed for effects on GI flora, discontinue if diarrhea, candidiasis or
rashes may occur.

7) Most beta-lactam antibiotics cause thrombophlebitis and periodical re-siting of the intravenous
cannulae is desirable.

8) Exercise caution in preterm infants.

Renal clearance of benzylpenicillin exceeds the glomerular filtration rate.

Penicillin is rapidly excreted by the kidneys and a minority by other routes
Tubular secretion accounts for about 90% of renal excretion
And glomerular filtration accounts for the remainder.
Hence the rate of renal clearance far exceeds the GFR

Ciprofloxacin should be avoided in children and pregnant and lactating women.

Main point
- Increases risk of tendon damage
 - Tendinitis with tendon rupture
- Possibility of arthropathy by damaging the growing cartilage

Other points
- Vomiting as a side effect - Could lead to hyperemesis since pregnant
- Also typically fluoroquinolone use is typically reserved for cases in which the benefits clearly
outweigh the risks.
- CYP 450 enzyme inhibitor. Possible drug interactions.

Doxycycline should not be administered together with calcium tablets

Co-administration of tetracyclines and divalent and trivalent cations can lead to chelation of the
tetracycline, with resultant poor absorption from the small intestine (or mouth in the case of
doxycycline). Hence resulting in subtherapeutic drug levels. Amount of drug insufficient to cause a
desired action.

A 60 year old man with chronic kidney disease is admitted with acute pyelonephritis. He has been
started on intravenous co-amoxiclav empirically. After 3 days his fever is still ongoing. The urine
culture and ABST report is traced and the ABST report is shown below.
Co-amoxiclav – resistant
Gentamicin – sensitive
Nitrofurantoin – sensitive
Ceftriaxone – sensitive
Ciprofloxacin – resistant
Cefotaxime – sensitive
What antibiotic will you choose to treat him? Give reasons for selecting the drug you mentioned over
the others.

Co-amoxiclav and Ciprofloxacin are resistant

Gentamicin primary cleared renally and must be avoided in renal impairment

Acute pyelonephritis - Upper UTI

Nitrofurantoin has little systemic effects
Use limited to lower UTI

So a 3rd generation cephalosporin cefotaxime or ceftriaxone

A 55-year-old man who has undergone an explorative laparotomy 24 hours ago develops acute severe
ischaemic chest pain post operatively. His ECG shows ST depressions in leads 1, aVL and V3-V6 and a
diagnosis of NSTEMI was made.

a) Discuss the problems that you might encounter when anticoagulating this patient.
- Interaction with antiplatelet used as DAPT in NSTEMI treatment
- Increased risk of post surgical bleeding

b) What are the factors that would determine your selection of anticoagulants?
Reversibility (UFH reversed by protamine sulfate)
Rapid short action (For this reason we prefer post MI)
Renal impairment (UFH suitable)
Incidence of HIT (Lower in LNWH)
Least monitoring and least bleeding risk (NOAC)
Cost effectiveness
Thromboprophylactic action

c) What anticoagulant would you use?

Heparin (Reversible + Rapid Action. Best choice post MI)

2. A 60-year-old woman with type 2 DM is found to have an irregularly irregular pulse of 110 bpm at
her routine clinic visit. ECG showed atrial fibrillation and her 2D Echo was normal.

a) What are the treatment goals in the management of atrial fibrillation in this patient?
3 goals
- Rate control
 - Rhythm control
- Stroke Prevention

b) Discuss, giving reasons, the drugs you would prescribe to meet each of the treatment goals
mentioned above.

Since she has AF

Rate control - Beta Blockers Nebivolol, Bisoprolol, Metoprolol Or Verapamil, Diltiazem
Rhythm control - Pharmacological cardioversion by IV Amiodarone (or flecainide)
Anticoagulation is needed prior to cardioversion
Stroke prevention- Warfarin (or rivaroxaban, apixaban)

c) What advice would you give regarding the use of drugs you prescribed?
Digoxin can control the rate only when sedentary
So limit exertion
Ensure compliance
Advice about SE
Monitor pulse and BP daily
Avoid grapefruit juice (amiodarone)
Important drug interactions warned
Monitor ECG and LFT frequently
3. Discuss how you would manage the following instances in a 55-year-old man who has been prescribed
warfarin for non-valvular atrial fibrillation.
a) ICH
b) INR of 5 found at routine follow up without any bleeding manifestations
c) INR of 8 and gum bleeding
1. A 50 year old otherwise healthy man is diagnosed with hypertension at a routine medical
examination. His blood pressure is 160/95mmHg.
1.1 What drug/s would you start to control his blood pressure?
Diuretics- Hydrochlorothiazide
ACE Inhibitors- Captopril
(Severe HTN- 160/95. 50 yrs. Previously healthy. We use dual therapy)

If DM ace inhibitors and ARBs.

If previous MI. Ace Inhibitor plus beta blocker
If no medical condition we can write one of the combinations

1.2 What would you monitor during the follow up?

Blood Pressure in two weeks
Thiazides in elderly patients especially require sodium monitoring

Suitability to increase dose

Renal artery stenosis requires especially monitoring.
ACEI contraindicated in bilateral stenosis (ok in unilateral)

Adverse effects
Diuretics- Gout, Weakness, Impotence, Glaucoma
ACEI- Angioedema, Rashes, Persistent dry cough, Fatigue
Patient compliance

2. A 60 year old woman presents with gradually worsening loss of appetite, shortness of breath and
bilateral leg oedema. Her blood pressure is 180/100mmHg. Her investigations are shown below.
Serum creatinine — 2.2 mg/d
Serum potassium — 4.9 mmol/L
Serum sodium 135 mmol/L
Urine full report
Protein +
Sugar +
Pus cells nil
Red cells nil
Organisms nil
Hemoglobin — 10 g/dL
Fasting blood glucose — 220 mg/dL

Ultrasound scan abdomen and pelvis bilateral small kidneys with diffuse renal parenchymal disease.
She is diagnosed with chronic kidney disease, hypertension and diabetes mellitus.

2.1 What drug/s would you start to control her blood pressure?
ACEI-Enalapril/ARB-Losartan
Calcium Channel Blockers- Verapamil

Are not contraindicated unless the patient has BL renal artery stenosis
Indicated in CKD due to its neuroprotective nature.
Thiazide Diuretics are contraindicated in CKD as It is ineffective in progressed Renal failure
Beta blockers interfere with carb metabolism causing hypoglycemia and the associated ANS response
masking its symptoms.
CCB are indicated in CKD and DM both. It also slows down atherosclerosis.
Both Systolic and Diastolic should be over the cutoff values to come to the conclusion of a Hypertensive
Emergency.

2.2 What would you monitor during the follow up?

3. A 35 year old woman who is being investigated for infertility is diagnosed with hypertension. Her
blood pressure is 160/100mmHg.
3.1 What drug/s would you start to control her blood pressure? Give reasons for your answer.
Methyldopa. Labetalol.
Methyldopa is preferred as it is safe for the fetus.
Patient is undergoing infertility treatment. She would wish to ensure future pregnancies are unaffected.

B blockers are used. They are non teratogenic, although IUGR is a complication. Laebtalol can preserve
fetal blood flow more in relation to other B blockers.

ACEI and ARBs are contraindicated as they are teratogenic.

Diuretics are not the first line of therapy as they are better avoided in a possible pregnancy.

Also nifedipine
Also prazosin

3.2 What advice would you give her with regard to drug therapy?
In pregnancy for the fetus to get adequate BS blood pressure must be controlled within a normal range.
Not too high and not too low as the fetus requires blood supply in a moderate amount.

4. A 55 year old man admitted with chest pain is diagnosed with non-ST Elevation acute coronary
syndrome (NSTE-ACS). His blood pressure is 200/110mmHg.
4.1 How would you control his blood pressure?
B Blocker
Calcium Channel Blocker
Diuretics

This patient BP cannot be dropped suddenly as it would lead to an acute ischemic stroke, which warrants
the usage of IV antihypertensives. To circumvent a steep decline in blood pressure.

4.2 What drugs are indicated for long term management of blood pressure in this patient?
Beta blockers have mortality benefits in ischemic heart disease.

Beta Blockers- Reduce risk of reinfection

ACEI/ARB- Prevent ventricular remodeling and reduce risk of HF

Nifedipine is wrong here. Zero marks. Causes a reflex tachycardia, worsening heart failure

1. A 67 year old man with a recent history of myocardial infarction undergoes a routine
echocardiogram. It shows an ejection fraction of 45%. The patient is asymptomatic.

1.1 What drugs would help to prevent development of symptomatic heart failure in this patient?
(Ejection Fraction is 45 percent, note the type of HF)
ACEI/ARB
(ARNI is a successful but expensive alternative)

1.2 What precautions do you need to take with regard to each of the drugs you mentioned above?
Precautions before prescribing ACEI ;
Find out contraindications for ACEI usage
(Dry cough, angioedema, renal failure, hyperkalemia,)
Precautions during prescribing ACEI ;
These drugs cause postural hypotension, these need to be administered at night. Ask them to lie down.
This reduces the effect of hypotension.

Precautions of B Blockers ;
Use cardioselective B Blockers. Others can worsen HF due to negative inotropic effects.

2. A 62 year old woman with hypertension, diabetes and congestive cardiac failure is on the following
drugs. Furosemide 40 mg BD Enalapril 5mg BD Carvedilol 12.5mg BD Spironolactone 25 mg mane
Digoxin 125 micrograms mane Metformin 1g BD Gliclazide 40mg BD

Describe, giving reasons, what you would do with regard to drug therapy in each of the following
situations.
2.1 At the routine clinic visit you detect that the patient’s blood pressure is 90/50 mmHg and the patient
reveals that he feels dizzy frequently.
Reduce the drug dose
Then reassess the patient in a clinical environment
To control symptoms and signs
Before stopping the drug as a whole

2.2 At the routine clinic visit you detect that the patient’s serum potassium is 6.1mmol/L. 2.3 At the
routine clinic visit the patient complains of severe loss of appetite and nausea and her pulse rate is 55
beats per minute.
Normal K level is 3.5-5.5
He has hyperkalemia
K levels must be controlled to prevent arrhythmias
All potential drugs that could cause hyperkalemia should be stopped
● ACEI
● K Sparing diuretics
● Digitalis glycosides
● Non selective B Blockers
Reasons that K could increase include
Old patient with multiple comorbidities
And T2DM
Renal impairment could be a likely co morbidity

Before managing hyperkalemia ;

Then temporarily stop K supplementation
Exclude pseudohyperkalemia
Check if the patient is symptomatic or not
Do investigations. ECG

2.4 The patient develops acute worsening of shortness of breath and leg oedema and is admitted to
hospital. She is diagnosed with acute decompensated heart failure.

She could have multiple organ failure

Metformin is not given here
It should be replaced with insulin

3. A 56 year old man admitted to hospital with an acute extensive anterior myocardial infarction,
develops acute shortness of breath on the second day. His pulse rate is 100 beats per minute, blood
pressure is 120/70mmHg and in the lung fields, there are bibasal fine crepitations. A diagnosis of acute
left ventricular failure is made.

3.1 Outline the pharmacological management of this patient.

3.2 Describe how his pharmacological management would differ, if his blood pressure is 85/50 mmHg.
A 26-year-old woman who presented with intermittent episodes of wheezing was diagnosed to have
mild asthma.

Describe the drug management of this patient. During the preceding month she has suffered frequent
episodes of shortness of breath and wheezing. . She has also experienced nocturnal symptoms 2-3 times
per week.
.

What details would you elicit with regard to her drug therapy?

What modifications would you suggest regarding her drug therapy?

Explain the pharmacological basis for the modifications 6 months later she presents to the ETU with an
acute exacerbation which is diagnosed as acute severe asthma. Her SaO2 is 92% of room air.

List 4 therapeutic agents, with their route of administration, which you would administer in the
immediate management of this patient.

Clinical evaluation an hour after the initial presentation reveals that the patient still has features of
severe asthma. What is the drug that is indicated now? State the precautions you need to take when
administering this drug.
Write a discharge prescription for this patient.

Compare and contrast the pharmacological properties of salbutamol, salmeterol and formoterol. 2.2
Explain how these differences relate to their clinical uses

A S-year-old boy who was having recurrent episodes of wheezing was brought to hospital with
wheezing and worsening difficulty in breathing. His SaO2 on admission was 9O% and rhonchi were
there on auscultation.

List the drugs that you would consider as the initial management along with mode of administration

Discuss the pharmacological basis on using the drugs you mentioned in 3.1 3.3 Discuss the long-term
drug management on discharge describing the pharmacological basis for the use of the drugs stated.

Discuss the differences in maintenance therapy and management of acute exacerbations of COPD when
compared to that of bronchial asthma.